Fibrinogen-like protein 2 (Fgl2) is a critical immunoregulatory factor, yet its precise roles in B-cell biology and mucosal immunity remain largely undefined. In this study, utilizing Fgl2-knockout (KO) mice, we identified novel B cell subsets in the spleen (SPL), predominantly characterized by IGHA clonal dominance. Employing an intestinal Trichinella spiralis (T. s) infection model and samples from patients exhibiting mucosal immune responses (the early stage of COVID-19 infection), we investigated the function of Fgl2 in mucosal immunity. We demonstrate that Fgl2 directly interacts with Receptor for activated C-kinase 1 (Rack1), thereby attenuating B cell receptor (BCR) signaling and metabolic activity by inhibiting AKT phosphorylation. Furthermore, the Fgl2 deficiency-induced expansion of marginal zone (MZ) B cells, germinal center (GC) B cells, and IgA+ plasma cells was effectively counteracted by in vivo Rack1 inhibition. Consistently, a Rack1 inhibitor also abrogated the enhanced activation of Fgl2-deficient B cells in vitro. Fgl2 deficiency also augmented early B cell activation, including B cell spreading, clustering, and signalosome recruitment, through upregulation of the DOCK8-WASP-actin axis. Our research uncovers an intrinsic role for Fgl2 in regulating BCR signaling, B cell differentiation, and mucosal immunity, elucidating a key underlying molecular mechanism.

Cancer is a highly complex and heterogeneous disease involving multiple pathophysiological events. Despite significant advances in modern medicine, the molecular mechanisms of cancer are still largely unknown. Omics methods have opened new avenues for identifying cancer biomarkers and elucidating disease pathogenesis. However, single-omics approaches only provide a limited understanding of biological mechanisms. The comprehensive analysis of multiomics data will provide useful insights for the pathogenesis, identification of therapeutic targets, and discovery of biomarkers in cancer. Here, we reviewed the disease signatures of cancer. We then reviewed the current state of multiomics biomarkers research in cancer. To further delineate the upstream pathogenic changes and downstream molecular effects of cancer, we also discuss the current strategies for integrating multiomics data using deep learning approaches. In addition, single-cell and spatial omics are being used to guide treatment strategies, risk assessment, and early diagnosis, as well as their potential impact on precision medicine. Despite the relative youth of the field, the development of single-cell and spatial omics promises to provide a powerful tool for elucidating the pathogenesis of cancer.

Autoimmune diseases (AIDs) arise from complex immune dysregulations involving multiple immune cell types, cytokines, and molecular mediators. Among these, microRNAs (miRNAs) have recently emerged as key regulators of leukocyte processes and are frequently dysregulated in AIDs. However, their role in disease pathophysiology remains poorly understood. In this study, we performed a comprehensive analysis of miRNA expression in three immune populations, namely, CD14⁺ monocytes, neutrophils, and CD8⁺ T cells, in multiple sclerosis (MS) and type 1 diabetes (T1D), two prototypical AIDs. Our results reveal distinct patterns of miRNA dysregulation in each cell type, with monocytes from T1D patients showing enhanced M1 polarization and supporting inflammatory vascular damage. On the other hand, CD8⁺ T cells from MS patients show profound alterations related to CD8⁺ T cell-fate commitment, apoptosis regulation, and migratory capacity. Notably, we identified miRNAs that regulate key transcription factors such as FOXP3, IRF4, and RORγt, potentially shaping T cell differentiation programs. Our results suggest that miRNA networks play a central role in orchestrating disease-specific dysregulation in AIDs. By elucidating these intricate regulatory mechanisms, our study provides a foundation for future therapeutic strategies targeting miRNAs in autoimmunity.

Corneal endothelial failure can cause blindness, with transplantation as the only treatment. Due to donor shortages, establishing robust methods for generating corneal endothelial-like cells (CECs) from induced pluripotent stem cells (iPSCs) is critical. Differentiation protocols included iPSC-to-CEC induction with or without neural crest cell differentiation. CECs directly differentiated from iPSCs demonstrated robust expression of CEC-specific markers and a hexagonal morphology. The wash-out protocol is a novel, efficient, noncytotoxic method for removing undifferentiated iPSCs and obtaining CEC populations with high purity. Single-cell sequencing data showed that iPSC–CECs with wash-out were similar to human primary CECs. In vivo transplantation of iPSC–CECs into a corneal endothelial dysfunction (CED) rabbit model demonstrated their safety and therapeutic efficacy, with improved corneal transparency. Notable recovery of corneal clarity in the CED model, without graft rejection, highlights the in vitro and in vivo potential of iPSC–CECs as a powerful source for clinical therapy in patients with CED. This work establishes an effective stem cell-based platform for producing corneal endothelium-like cells with clinical-grade quality, offering a scalable and regenerative alternative to conventional transplantation.

Homeobox genes constitute a large family of transcription factors that act as master regulators involved in multiple fundamental processes such as development and cell differentiation. Consequently, these transcription factors perform diverse functions throughout human life. However, dysregulation of homeobox gene expression, through pathogenic variants or epigenetic alterations, has been increasingly associated with a wide range of human disorders. In particular, correlations between homeobox genes and various types of cancer have been documented in hundreds of studies. This review provides an integrative overview of homeobox gene biology, summarizing their classification as well as their physiological and pathological roles across noncancerous and cancerous diseases. Particular attention is given to how dysregulation of gene expression contributes to various noncancerous diseases (e.g., congenital, metabolic, and neurodegenerative disorders) and to malignancies, especially the five highest incidence of cancers, with a detailed focus on lung cancer, where epigenetic mechanisms play a central role in tumor progression.

Chimeric antigen receptor T (CAR-T) cell therapy, originally developed for hematologic malignancies, has emerged as a transformative candidate for systemic rheumatic diseases and autoimmune disorders (AIDs). Its unique efficacy in refractory AIDs relies on depleting autoreactive B cells and driving antigen-naïve immune reconstitution, achieving durable drug-free remission in early-phase trials. Despite promising clinical and serological responses lasting 2–5 years without long-term immunosuppression, the field faces unmet needs: complex manufacturing, limited tissue penetration, antigen escape, immunological sequelae, and lack of predictive biomarkers. Existing reviews predominantly focus on oncology adaptations or isolated technical aspects, lacking systematic integration of mechanisms, challenges, and precision-oriented innovations for rheumatic diseases. This review comprehensively summarizes CAR-T's action mechanisms in AIDs, analyzes core clinical challenges, and highlights emerging strategies—including universal/in vivo-generated CAR-T cells, multitargeted/logic-gated designs, organ-homing engineering, and rational combinations with tolerance-enhancing agents. It further emphasizes multiomics integration (single-cell transcriptomics, spatial mapping, B-cell receptor/T-cell receptor repertoire analysis) for patient stratification and relapse prediction. By bridging mechanism-driven engineering with clinical translation, this work provides an actionable framework to advance CAR-T toward functional immune reset, enabling precision immunotherapy for refractory rheumatic diseases and AIDs.

Sepsis remains a leading cause of global mortality, characterized by uncontrolled inflammation and multi-organ dysfunction. Galectin-3 (Gal-3) is a damage-associated molecular pattern (DAMP) protein that amplifies inflammatory cascades during sepsis and represents a potential therapeutic target. We conducted an integrated translational investigation combining clinical observation (87 septic patients, 27 healthy volunteers) with preclinical Gal-3 removal using an anti-Gal-3 apheresis column in two sepsis models: a rat cecal ligation and puncture (CLP) model (n = 48) and a porcine lipopolysaccharide (LPS)-induced model (n = 31). Mechanistic assessments included serum testing, multi-omics profiling, invasive hemodynamic monitoring, and histopathology. Patients with sepsis exhibited markedly elevated Gal-3 levels (p < 0.001), and survivors showed progressive Gal-3 decline compared with non-survivors (p < 0.01). Gal-3 removal significantly improved survival in rats (57.1% vs. 25.0%, p = 0.003) and pigs (68.8% vs. 26.7%, p = 0.004). Treatment attenuated neutrophil activation and tissue infiltration, preserved endothelial barrier integrity, and modulated pro-survival and hypoxia-response signaling pathways, accompanied by reduced vasopressor requirements and pulmonary edema. Collectively, these findings demonstrate that Gal-3 removal improves survival and reduces organ damage in preclinical sepsis models in association with coordinated neutrophil modulation and endothelial barrier preservation, highlighting Gal-3 as a promising therapeutic target in sepsis.

Pulmonary fibrosis is a chronic and progressive interstitial lung disease with limited treatment options aside from lung transplantation. Bleomycin (BLM)-induced lung injury is the most commonly used experimental model to mimic the key pathological features of human pulmonary fibrosis, which include an early inflammatory phase and a later fibrotic phase. Neutrophil infiltration and M2 macrophage activation are key events in these stages, respectively. However, the molecular mechanisms by which BLM triggers pulmonary inflammation and fibrosis remain incompletely understood. In this study, we found that BLM treatment induced ROS-mediated oxidative damage in the lungs, leading to an inflammatory microenvironment and the release of oxidized mitochondrial DNA (oxid-mtDNA). Oxid-mtDNA was shown to contribute to the early inflammatory response by promoting neutrophil recruitment and enhancing macrophage polarization, which subsequently drove tissue remodeling and fibrosis. Notably, direct injection of oxid-mtDNA into the lungs recapitulated the fibrotic features observed in the BLM model. Furthermore, studies using STING- and NLRP3-deficient mice demonstrated that loss of either pathway significantly attenuated BLM-induced inflammation and fibrosis, implicating their involvement downstream of oxid-mtDNA signaling. Collectively, our findings identify oxid-mtDNA as a critical mediator linking oxidative injury to immune activation and fibrotic remodeling in the lung, offering new insights into pulmonary fibrosis pathogenesis and potential therapeutic targets.

Extracellular and membrane proteins serve important roles. They manage cellular communication, structure support, and immune defense. When they malfunction, it cause many diseases like cancer, neurodegeneration, and cardiovascular disorders. Targeted protein degradation (TPD) is a promising therapeutic strategy and aims to remove these faulty proteins. This approach goes beyond traditional drugs, which only block the active site of proteins. The aim of TPD is to entirely remove the targeted proteins in cells. This review began with explaining the structure and functions of extracellular and membrane proteins, highlighting their connection with disease. It then went on to discuss new strategies for their degradation. These emerging strategies include those that take advantage of cell-surface receptors to target lysosomes, intracellular lysosomal sorting tools, E3 ligases, and nanoparticle-based systems. A comparison of different TPD tools was also provided. Discussion compared strengths and weaknesses of approaches with small molecules, antibodies, nanobodies, and aptamers. Finally, the review outlined future directions for advanced TPD strategies. Next steps would be the combination of degraders with therapeutic antibodies. Another research interest is the utilization of tissue-specific receptors from genetic databases. Moreover, the application of TPD to immune and neurodegenerative diseases is also a critical goal for the future.

Enterovirus A71 (EV-A71) is recognized as the primary causative agent of hand, foot, and mouth disease (HFMD) and is prevalent worldwide. However, the precise pathogenic mechanisms of EV-A71 remain unclear, and specific drugs targeting it have yet to be successfully developed. To explore the mechanisms underlying EV-A71 pathogenesis and to identify potential therapeutic opportunities, we performed a comprehensive proteogenomic characterization of muscle tissues from BALB/c mice infected with EV-A71, integrating transcriptomic, proteomic, and phosphoproteomic analyses. Our results showed that phagosome, complement, and coagulation cascade pathway-related molecules were activated, and the expression of cell growth-related molecules was downregulated. Concurrently, a rapid activation of the neutrophil extracellular trap pathway was observed at the protein level. Additionally, we mapped the global phosphorylation profiles to dysregulated kinases, predicting 32 drugs corresponding to 27 kinases. We found that kinase inhibitors have antiviral activity in vitro; vandetanib, nintedanib, dasatinib, avitinib, and nilotinib can inhibit virus replication in mice to some extent. Overall, this study provides a multi-omics resource for elucidating EV-A71-induced alterations in target tissues and for linking omics-based target discovery with drug screening and functional validation, providing new insights into both pathogenesis and therapeutic exploration.

Fospropofol disodium (fospropofol), a water-soluble prodrug of propofol, reduces injection pain and anesthetic requirements but frequently causes paresthesia. Intravenous lidocaine has been shown to alleviate dexamethasone-induced paresthesia, yet its effect on fospropofol-related symptoms remains uncertain. We combined preclinical and clinical studies, first evaluating the safety and pharmacological changes of fospropofol premixed with lidocaine through in vitro and in vivo experiments and then conducting a randomized controlled trial in adult surgical patients to evaluate whether the lidocaine premixing strategy affects the occurrence of fospropofol-induced paresthesia. In the preclinical study, the findings indicated that mixture of fospropofol and lidocaine remained physicochemically stable, with faster onset and longer sedation duration compared with fospropofol alone, without additional adverse effects. In the clinical trial, 74 patients received fospropofol dissolved in either 20 mL of normal saline or 0.75% lidocaine and 72 were included in the primary outcome analysis of paresthesia. This adverse reaction occurred in 83.3% of patients in both groups, mainly within 40–60 s after administration. No group differences were observed in plasma inflammatory markers and phosphate; however, phosphate levels increased postadministration in both groups. This study provides important guidance for clinical practice, showing that premixing lidocaine does not effectively alleviate paresthesia induced by fospropofol.

Liquid–liquid phase separation (LLPS) has emerged as a fundamental physicochemical principle that organizes macromolecules into dynamic, membraneless condensates. These assemblies are increasingly recognized as critical regulators of diverse cellular processes. Notably, both viruses and their hosts exploit LLPS to optimize their respective strategies for replication and defense, forming a dynamic interplay centered around phase separation. However, a comprehensive mechanistic understanding of how LLPS modulates the dynamic viral–host battle, and how this knowledge can be leveraged for therapeutic development, remains an active area of investigation. This review systematically explores the dual roles of LLPS in viral infection and antiviral immunity. We detail how viruses hijack LLPS to form replication factories and inclusion bodies that enhance entry, replication, and immune evasion. Conversely, we explore how host cells leverage LLPS to assemble potent immune signaling hubs, such as those nucleated by cGAS–STING, NLRP6 inflammasomes, and T/B-cell receptor microdomains, to amplify antiviral responses. Furthermore, we critically evaluate emerging therapeutic strategies that target these phase separation interfaces. By integrating recent advances across virology, immunology, and biophysics, this review establishes a unified framework for understanding and targeting LLPS in viral infectious diseases, offering new perspectives for future basic research and clinical intervention.

Chronic hepatitis B (CHB) remains incurable due to the immune system's tolerance toward the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy. CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (Cohort 1) or ADV combined with interferon-alpha (IFN-α) (Cohort 2). Additionally, a third cohort received the THRIL-GM-Vac regimen: three low-dose GM-CSF injections followed by one dose of the HBV vaccine, alongside standard treatment. THRIL-GM-Vac treatment (Cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants, and 8.7% HBsAg clearance in Cohort 3 compared to 0% and 4.17% in Cohorts 1 and 2, respectively. Furthermore, THRIL-GM-Vac significantly reduced HBV-specific tolerogenic T cells (Tregs), explaining the sustained HBsAg decrease. Upregulation of anti-HBV T cell responses confirmed THRIL-GM-Vac's ability to disrupt HBV tolerance and enhance HBsAg-specific cellular immunity. This suggests its potential effectiveness in treating individuals with moderate to low HBsAg levels. THRIL-GM-Vac treatment in Cohort 3 resulted in 8.7% HBsAg clearance alongside Treg depletion and enhanced anti-viral T cell responses. These findings present a promising strategy to overcome immunotolerance and potentially combat chronic HBV infection.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of premature mortality, but data on sex differences in mortality remain limited. We compared the overall, nonliver-related, and liver-related mortality rates per 1000 person-years in MASLD patients by sex. Propensity score matching (PSM) yielded 3579 pairs of females and males with balanced characteristics from a cohort of 8517 MASLD patients (53.1% female, 46.6% male) seen at Stanford University Medical Center (1995–2023). In the total PSM cohort, the overall (12.68 vs. 12.92), nonliver-related (11.43 vs. 11.60), and liver-related (1.25 vs. 1.32) mortality rates were similar between males and females. However, in age-stratified analyses, females had higher overall (7.99 vs. 4.95, p = 0.02) and nonliver-related (7.20 vs. 4.71, p = 0.05) mortality rates among younger (≤50 years) patients, with opposite direction among the older group with higher overall (21.40 vs. 16.51, p = 0.02) and nonliver-related (19.02 vs. 14.80, p = 0.04) mortality rates in males. In Cox regression analyses, male sex was associated with lower risks of overall and nonliver-related mortality (adjusted hazard ratio [aHR] 0.59 and 0.61) among patients ≤50 years, but with higher risks among those >50 years (aHR 1.32 and 1.30). Sex and age should be considered in the management strategies for people with MASLD.

Pancreatic cancer is highly refractory and aggressive, with cancer stem cells (CSCs) being primarily responsible for its metastasis and chemoresistance. Deregulated cellular bioenergetics is a hallmark of cancer cells. However, the influence of bioenergetics on the maintenance of pancreatic CSC stemness and its underlying mechanisms have not been fully elucidated. In this study, pancreatic CSCs, isolated either by sorting ALDH⁺ subpopulation or enriching serially passaged tumorspheres from pancreatic cancer cells and PDX model, exhibited active mitochondrial complex I activity and increased oxidative phosphorylation. Complex I maintains stemness and tumorigenicity through its core subunit, NDUFS1. NDUFS1-mediated pancreatic CSC stemness is reinforced by high expression of CD147, which promotes pSTAT3^Tyr705-mediated NDUFS1 transcription. To promote stemness, CD147-NDUFS1 initiates SIRT1-DNMT1 metaboloepigenetic signaling, decreasing promoter hypomethylation and increasing the mRNA expression of the stem cell transcript factor PAX2. Moreover, NDUFS1 and CD147 expressions were highly correlated in pancreatic cancer tissues, and their co-expression was significantly associated with poor patient survival. Taken together, our study provides evidence that mitochondrial complex I functions as a key player in CSC stemness maintenance through NDUFS1-mediated retrograde metaboloepigenetic signaling. Blocking a key regulator of mitonuclear communication by targeting CD147 may be a novel therapy for pancreatic cancer.

Covert mpox virus (MPXV) infection among people living with HIV (PLWH) remains poorly understood. This study aimed to investigate undetected MPXV infections through seroepidemiological analysis. We recruited 148 PLWH during July 2–9, 2023 (baseline), with 60 and 148 participants returning for 4- and 14-month follow-ups, respectively. PCR testing showed that all saliva and blood samples were negative for MPXV-DNA. The titers of IgG, IgA, and IgM were evaluated using ELISA with virions. MPXV-IgA and IgM were undetectable, 15 participants born before 1980 had low MPXV-IgG at baseline. At 14 months, 10 participants (6.8%) showed increased MPXV-IgG titers. All seroconverters had detectable neutralizing antibodies, and nine were MPXV-IgA positive. Further results showed that IgG seropositivity against MPXV proteins (A29L, A35R, B6R, E8L, H3L, and M1R) ranged from 0% to 80%, while IgA seropositivity ranged from 0% to 60% among the 10 participants at the 14-month. The B6R and E8L combination showed IgG detection comparable to whole virions, while E8L and H3L combination increased IgA seropositivity to 70%. The occurrence of MPXV covert infection among PLWH underscores the need to improve surveillance strategies in the community. The presence of MPXV-IgA in blood may offer a preliminary temporal signal of MPXV infection.

Antibiotic resistance is a significant global health challenge that demands innovative strategies to combat resistant pathogens. Spices, known for their culinary and medicinal qualities, have emerged as promising sources of antimicrobial agents due to their rich content of potent bioactive phytochemicals. Compounds such as flavonoids, phenolics, alkaloids, and terpenoids exhibit strong antibacterial, antifungal, and antiviral activities. These phytochemicals target microbial cell walls, membranes, and metabolic processes, effectively inhibiting pathogen growth and survival. Additionally, their ability to disrupt biofilms and synergize with conventional antibiotics enhances their potential to counter resistance mechanisms. This review examines the mechanisms and dissemination of antimicrobial resistance, the antimicrobial properties of spices and their phytochemicals, focusing on their modes of action, efficacy against multidrug-resistant pathogens, specific extraction methods for each phytochemical, synergism with traditional antibiotics, safety and toxicological concerns, future research directions, and challenges in the widespread use of these spice-derived compounds. It highlights the vast array of antimicrobial solutions derived from these spices and their natural phytochemicals, offering sustainable and effective means to address the escalating threat of antibiotic resistance.

Early maturation poses a considerable health challenge worldwide. We aim to quantify the global disease burden attributable to early maturation in 2021. We calculated sex-specific and region-specific population attributable fractions (PAFs) of diseases through meta-analysis and Mendelian randomization. The age-standardized incidence rate (ASIR) with 95% uncertainty intervals (UIs) of these diseases, stratified by sex, age, and development status were estimated using the Global Burden of Diseases database. Asthma, Type 2 diabetes, ischemic heart disease, stroke, uterine cancer, testicular cancer, and depression was causally related with early maturation, with PAF ranging from 7.7% for uterine cancer to 0.8% for Type 2 diabetes. About 11.2 million new attributable cases occurs, with an ASIR of 210.1 (95% UI 155.1–280.7) cases per 100,000, with higher PAF in females (3.4%) than in males (2.3%). The ASIR was highest in North America (405.5, 309.0–526.3 cases per 100,000) and lowest in East Asia and the Pacific (120.8, 89.6–160.3 cases per 100,000). More developed regions showed 1.4 times higher incidence burden (ASIR 268.5, 199.6–356.6 cases per 100,000) than less developed regions. Therefore, regional adoption of effective public health interventions to alleviate early maturation, notably for females in more developed regions, has enormous potential to reduce worldwide disease burden.

Pancreatic cancer remains highly lethal, largely due to late diagnosis and limited efficacy of treatments. Improving first-line treatment selection and patient monitoring requires novel, non-invasive biomarkers beyond carbohydrate antigen 19-9 (CA19-9) and imaging. This study investigates epigenetic biomarkers from liquid biopsy with prognostic and predictive potential in metastatic pancreatic ductal adenocarcinoma (PDAC; mPDAC). Genome-wide methylation profiling of cell-free DNA (cfDNA) from healthy individuals and stage IV mPDAC patients identified 13 gene-associated CpG sites with significantly altered methylation patterns. ddPCR validation confirmed consistent methylation differences in lymphocyte transmembrane adaptor 1 (LAX1), nuclear receptor subfamily 3 group C member 1 (NR3C1), and RCAN3 between healthy and patient groups. Elevated LAX1 and RCAN3 methylation and reduced NR3C1 methylation at diagnosis were associated with poor prognosis and correlated with high-risk circulating biomarker profiles, including CA19-9 levels, RAS MAF (mutant allele fraction), cfDNA concentration, and cfDNA fragmentation. Notably, baseline NR3C1 methylation levels predicted response to first-line FOLFIRINOX-based treatment with an acceptable 75% sensitivity and a high specificity of 92.86%. These findings highlight the clinical significance of cfDNA methylation as a minimally invasive biomarker source, emphasizing LAX1, NR3C1, and RCAN3 as prognostic biomarkers in mPDAC. Specifically, baseline NR3C1 methylation emerges as a promising predictor of treatment response, supporting personalized therapeutic strategies in mPDAC.

Oncolytic adenovirus (OAd) therapy is one of the effective treatment strategies for solid malignant tumors, and E1A is a requirement for adenovirus replication. Thus, it is very important to study how E1A regulates adenovirus replication. The p300 and E1A expression were detected by Western blot. The viral replication of OAd was detected by virus replication assay. The interaction between E1A and p300 was analyzed by immunofluorescence and immunoprecipitation assays. The therapeutic effect of OAd-shp300 was analyzed by MTT assay and animal experiments. The results indicated that OAd infection or E1A overexpression could reduce p300 expression, implying that OAd might reduce p300 expression via E1A, and p300 knockdown could enhance viral replication and cell cytotoxicity of OAd. Furthermore, E1A promoted viral replication of OAd via mediating p300 ubiquitination degradation to inhibit the IFI16/STING/IRF3/IFN-β signaling pathway. Additionally, OAd-shp300 induced highly efficient viral replication and potent antitumor activity both in vitro and in vivo. In this study, OAd can reduce p300 expression by promoting its ubiquitination via E1A, thereby enhancing viral replication and cell cytotoxicity. Therefore, this study can provide a biomarker for screening patients who are sensitive to OAd and new ideas for clinical tumor treatment.

This phase II trial evaluated the efficacy and safety of combining niraparib with the PD-1 inhibitor HX008 in patients with metastatic breast cancer who had germline DNA damage response (DDR) mutations. The study included 37 patients, divided into a primary cohort of HER2-negative individuals with germline BRCA1/2 or PALB2 mutations (n = 29) and an exploratory cohort of patients who were either HER2-negative with other DDR mutations, had brain metastases, or were HER2-positive (n = 8). The main cohort achieved an objective response rate (ORR) of 76% and a disease control rate (DCR) of 97%, with a median progression-free survival (PFS) of 7.3 months. The exploratory cohort had an ORR of 25% and a DCR of 75%, while patients with brain metastases showed a 40% ORR. Among treatment-related adverse events of Grade 3 or higher, the most frequently observed were anemia (35.1%), thrombocytopenia (10.8%), and neutropenia (8.1%). No treatment-related deaths were reported. Somatic XPO1 mutations correlated with better response. Somatic TP53 mutations significantly correlated with shorter PFS, while ASXL1 mutations correlated with longer PFS. This chemotherapy-free regimen demonstrates promising efficacy and a tolerable safety profile in patients with metastatic breast cancer and germline DDR mutations, providing a novel therapeutic option for this patient population, even those with brain metastases.

Chronic pain is a globally prevalent and complex condition, encompassing three primary subtypes, that is, nociceptive, neuropathic, and nociplastic, each with distinct biopsychosocial mechanisms. Chronic pain was historically viewed as a monolithic symptom and managed with opioid-centric models, causing widespread therapeutic failure. While recognition of its heterogeneity has driven a paradigm shift toward precision medicine, tailoring multimodal strategies to the dominant pain mechanism, critical challenges persist. These include difficulty in identifying treatable root causes, limited long-term efficacy of therapies, and significant side-effect burdens. To address these gaps, this review systematically synthesized contemporary knowledge, predominantly from the last decade, on the molecular mechanisms, risk factors, diagnostic frameworks, and therapeutic modalities for chronic pain, framed by its pathophysiological subtypes. Furthermore, it explored two novel frontiers aimed at advancing personalized pain medicine. First, it proposed cold atmospheric plasma as an innovative therapeutic intervention capable of modulating key molecular pathways underlying diverse pain manifestations. Second, it introduced an original neurobiological model positing the hippocampus as a putative sensor for nociplastic pain, interfacing with higher-dimensional information fields. These insights may offer transformative potential for refining diagnostic and therapeutic strategies, potentially revolutionizing the management of chronic pain.

Isocitrate dehydrogenase (IDH)–mutant astrocytomas are recognized as a single molecular entity spanning CNS WHO Grades 2–4, and clinical behavior is shaped by early lineage-defining alterations (IDH1/2, ATRX, TP53) and by later events linked to malignant transformation (e.g., CDKN2A/B homozygous deletion). Despite integrated grading, substantial prognostic heterogeneity is observed, and treatment decisions are increasingly informed by multidomain risk stratification rather than grade alone. In this review, contemporary molecular classification and diagnostic principles are summarized, and pragmatic risk models integrating clinical factors, histomolecular features, and imaging/radiomics markers are synthesized. Standard therapies (maximal safe resection, involved-field radiotherapy, and alkylating chemotherapy) are reviewed in a grade-spanning, risk-adapted framework. Therapeutic advances are highlighted, with particular emphasis on brain-penetrant IDH inhibition (vorasidenib) and on emerging strategies including vaccines, checkpoint combinations, epigenetic modulation, metabolic and microenvironment targeting, and novel delivery platforms. Mechanisms of resistance and recurrence, including therapy-driven hypermutation and clonal evolution, are discussed alongside practical salvage considerations. Finally, future directions in trial design, survivorship-oriented endpoints, and biomarker-driven monitoring are outlined. A trajectory-based paradigm is emphasized in which neurocognitive preservation, time to radiotherapy or chemotherapy, and patient-reported outcomes are prioritized while durable disease control is pursued across decades-long survivorship.

The value of microbial metabolites in prognosis and treatment response prediction in patients with nasopharyngeal carcinoma (NPC) remains unclear. Here, through the untargeted metabolomic analysis of plasma in 48 paired NPC patients with or without tumor relapse, we identified distinct circulating metabolite atlases between NPC patients with different prognoses. We used bootstrap least absolute shrinkage and selection operator (LASSO) on a penalized Cox regression model to select metabolites and constructed a metabolite risk model comprising four microbial metabolites in a training cohort (n = 202), and validated it in an independent test cohort (n = 201) and an external validation cohort (n = 180). The model stratified patients into three risk groups. Patients in the low-risk group had optimal DFS, DMFS, and OS, compared with those in the intermediate-risk group. High-risk patients had poor survival across all clinical endpoints. Furthermore, patients in the intermediate-risk group could benefit from induction chemotherapy. In addition, we generated a nomogram integrating the risk model, N stage, and plasma EBV-DNA load, which further enhanced the predictive accuracy of the metabolite risk model. Collectively, we developed and validated a robust predictive model based on serum metabolites, promoting risk stratification and enhancing treatment outcomes in patients with NPC. We identified distinct circulating metabolite atlases between NPC patients with different prognoses in the training cohort (n = 202). A risk model, comprising four microbial metabolites, was developed to stratify patients into three risk groups. Patients in the low-risk group had optimal DFS, DMFS, and OS, compared with those in the intermediate-risk group. High-risk patients had poor survival across all clinical endpoints. Findings were validated using an independent test cohort (n = 201) and an external validation cohort (n = 180). Specifically, a nomogram integrating the risk model, N stage, and plasma EBV-DNA load enhanced predictive accuracy. Moreover, patients benefited from induction chemotherapy with improved survival in the intermediate-risk group, but not in the low-risk and high-risk groups.

Anti-PD-1/PD-L1 therapy has achieved promising success across several tumor types; however, its efficacy is still far from satisfactory in non–small cell lung cancer (NSCLC). Combining therapies have been attempted to synergize anti-PD-1/PD-L1 therapy through activating antitumor response. Previously, we convinced the role of sulforaphane (SFN) in regulating tumor immune microenvironment (TME) to enhance antitumor response. Consistently, here we observed combining SFN with chemotherapy and anti-PD-1 therapy achieved the best tumor suppression versus other treatments in mouse models bearing Lewis lung carcinoma cells. Further, a clinical trial (KY-2021-0266) was performed, and the disease control and objective response rates were higher in the experimental group (SFN combined anti-PD-1 antibody and chemotherapy group, n = 30) compared with the control group (anti-PD-1 antibody combined chemotherapy group, n = 30) (100% vs. 93.3% and 86.7% vs. 60.0%, respectively). Moreover, the median progression-free survival was longer (19 vs. 9.5 months, respectively) in the experimental group. After treatment, antitumor response was enriched, while CD8-related function markers were elevated and myeloid-derived suppressor cell/M2-related markers were reduced in the experimental group. Two spurious progressions were observed in the experimental group. In conclusion, this synergistic effect suggests that SFN may be a promising immunosensitizer and a treatment option in NSCLC.

The axon initial segment (AIS) is a specialized neuronal microdomain that serves as a physical diffusion barrier, separating the axon from somatodendritic compartments. As a highly plastic structure, the AIS dynamically regulates neuronal excitability and contributes to circuit homeostasis. Recent advances in super-resolution imaging and disease modeling have expanded our understanding of its role in neurodevelopment and neurodegenerative disorders. This review first systematically outlines the molecular architecture of the AIS, including its cytoskeletal scaffolds and ion-channel complexes. Then, we discuss AIS plasticity, ranging from activity-dependent alterations to the molecular mechanisms that regulate it, and to its key biological functions, such as its role in action potential initiation, neuronal polarization, subcellular organelle sorting, and neural circuit excitability. We further highlight emerging evidence that AIS disruption represents an early pathological event in neurodegenerative and neuropsychiatric disorders. By integrating physiological and pathological perspectives, and by evaluating emerging biomarker strategies and therapeutic interventions, this review outlines directions and challenges for future AIS-targeted therapies. Meanwhile, it summarizes key experimental and potential clinical tools for future AIS research. Overall, elucidating the molecular mechanism of the AIS in both health and disease provides a deeper understanding for advancing the diagnosis and treatment of neurological diseases.

Although immunochemotherapy sheds light on neoadjuvant strategies, about two-thirds of patients still respond poorly to perioperative chemoimmunotherapy. Hence, it is crucial to investigate the underlying response mechanism to improve the prognosis of these patients. In this study, we utilized paired pre- and post-neoadjuvant immunochemotherapy samples from non-small-cell lung cancer (NSCLC) patients with single-cell RNA and T-cell receptor (TCR) sequencing to characterize the dynamic changes of T cells in tumor microenvironment. Within nine enrolled patients with distinct pathological assessments, we identified bi-directional mechanisms associated with their pathological responsiveness. One is mediated by a batch of CD8⁺ T-cell subsets such as effector memory T cells (Tem), effector T cells (Teff), tissue-resident memory T cells (Trm), and exhausted T cells (Tex), exhibiting higher TCR clonality and diversity in responders. CD8⁺ Tem cells with both novel and pre-existing TCR clonal expansion patterns particularly contributed to improved pathological responses. The other mechanism is through inhibitory Tregs, which showed more novel clonal expansion and enhanced functional profiles in nonresponsive tumors. In conclusion, our findings proposed the bidirectional characteristics of T-cell dynamics for in-depth interpretation of responding mechanisms to neoadjuvant immunochemotherapy of NSCLC.

The central nervous system (CNS) maintains homeostasis and immune surveillance through a recently defined brain-wide clearance network: the glymphatic–lymphatic axis. This system couples the intramural glymphatic pathway, responsible for convective fluid transport and parenchymal waste removal, with the meningeal lymphatic vessels (MLVs), which serve as the critical efferent route to the peripheral immune system. This review delineates the structural and functional foundations of each component, their regulatory dynamics, including the roles of sleep and aging, and their synergistic interplay in maintaining fluid balance, clearing metabolic waste, and facilitating neuroimmune communication. Mounting evidence identifies the dysfunction of this integrated axis as a common pathological mechanism across a spectrum of neurological disorders. We highlight its pivotal role in three key paradigms: acute injury (stroke), chronic proteinopathy (Alzheimer's disease, AD), and autoimmune dysregulation (multiple sclerosis, MS), where impaired clearance and maladaptive immune responses are central, recurring themes. The review critically evaluates emerging translational strategies aimed at therapeutically modulating this axis, including pharmacological targets (VEGF-C, Piezo1 agonists), noninvasive neuromodulation (photo-biomodulation, PBM), and surgical interventions (lymphaticovenous anastomosis, LVA). This synthesis positions the glymphatic–lymphatic axis as a fundamental physiological network and a pivotal target for novel interventions, outlining key future research directions in neurology.

Metal–organic frameworks (MOFs) have emerged as a promising class of nanomaterials for drug delivery due to their exceptionally high surface area, tunable pore structures, and chemical versatility. However, conventional experimental techniques cannot fully capture atomic-scale drug–carrier interactions or transient diffusion processes within MOF pores. Molecular dynamics (MD) simulation, a computational technique that tracks atom-level movements over time, has thus become indispensable for probing these microscopic mechanisms. This review introduces the fundamentals of MD simulation and comprehensively examines how MD simulation reveals drug adsorption mechanisms, functionalization effects, and release kinetics in MOF-based delivery systems. Then, it systematically compares major MOF families including isoreticular metal–organic frameworks, zeolitic imidazolate frameworks, Materials of Institute Lavoisier Frameworks, University of Oslo Frameworks, and porous coordinated networks and highlight their distinct host–guest interactions and stimuli-responsive behaviors. The integration of multiscale modeling and machine learning further enhances predictive capabilities for carrier design. By establishing MD simulation as a fundamental tool for understanding nanoscale drug–carrier interactions, this review provides a theoretical foundation for developing efficient, stable, and responsive MOF-based nanocarriers, advancing the field of precision nanomedicine.

Glioblastoma (GBM) is a highly aggressive, therapy-resistant brain tumor with inevitable recurrence despite maximal multimodal treatment. Increasing evidence suggests that this intractability arises from coordinated cellular programs rather than a single dominant pathway. Central to these programs are glioma stem-like cells (GSCs), which sustain self-renewal, phenotypic plasticity, and resistance to genotoxic and metabolic stress, and yet the molecular basis of their long-term tumor-propagating capacity remains incompletely understood.

Here, we synthesize recent advances to propose an integrated conceptual framework—the Triadic Nexus—in which GSC stemness, telomere maintenance mechanisms, and metabolic reprogramming function as a self-reinforcing regulatory system. We review how telomerase reactivation versus alternative lengthening of telomeres (ALT) differentially shape genomic stability, immune signaling, and metabolic states and how metabolic plasticity feeds back to regulate stemness and telomere-associated stress responses. Drawing on single-cell, spatial, and multi-omics studies, we highlight how these interdependent axes collectively sustain therapy resistance and tumor recurrence.

Finally, we discuss the translational implications of the Triadic Nexus, emphasizing rational combinatorial therapeutic strategies and biomarker-guided patient stratification based on telomere and metabolic signatures. By unifying stemness, telomere biology, and metabolism into a mechanistically testable model, this review provides a systems-level framework for understanding GBM persistence and guiding next-generation therapeutic interventions.

Intravenous thrombolysis (IVT) is the treatment with the highest level of evidence for acute ischemic stroke, but about half of patients fail to achieve a favorable prognosis. This study (NCT05598658) proposed a treatment strategy of adjunctive two sessions of remote ischemic conditioning (RIC) within 24 h after IVT, and evaluated the effects through cerebral autoregulation (CA) and brain-injury biomarkers. Patients were randomized (1:1) to the RIC or sham-RIC groups, which received 200 and 60 mmHg RIC, respectively, at 6 and 18–24 h after IVT. CA was assessed at 2 and 7 days after IVT and serum brain-injury biomarkers were evaluated at 24 h after IVT. The primary outcome was CA at 2 days after IVT. A total of 100 patients were randomized to the RIC or sham-RIC group. Ipsilateral CA was significantly higher in the RIC group than in the sham-RIC group at 2 days (β: 14.970 [95% confidence interval, 7.741–22.199; p < 0.001]) and 7 days after IVT. Simultaneously, neuron-specific enolase level at 24 h after IVT was significantly lower in the RIC than the sham-RIC group. These results suggest that adjunctive two sessions of RIC within 24 h after IVT can effectively exert neuroprotective effects in patients with IVT.

Both PRMT5 and EphA2 proteins are overexpressed and play a crucial role in multiple cancers, and have been used as targets to develop new anticancer drugs. However, the function and significance of the PRMT5–EphA2 interaction are unclear. Here, we report that PRMT5 bound to EphA2, catalyzed the dimethylation of EphA2 at arginine 816, and then stabilized EphA2 via inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC) cells. Functionally, PRMT5 promoted in vitro and in vivo NPC stem cell properties by methylating and stabilizing EphA2. Based on the interacting regions of PRMT5 and EphA2 proteins, we developed a 20 amino acid-long PRMT5-derived peptide, P20, which disrupted the connection of PRMT5 with EphA2, degraded EphA2, and suppressed NPC stem cell properties in vitro and in mice. Moreover, the expression levels of PRMT5 and EphA2 in the NPC tissues were significantly higher than those in the normal nasopharyngeal mucosal tissues, and both proteins for predicting the patient's prognosis are superior to individual proteins. Our findings suggest that PRMT5 methylates and stabilizes EphA2 to promote NPC stem cell properties, and the PRMT5-derived peptide P20 can serve as a novel strategy for targeting EphA2 degradation and inhibiting NPC stem cell properties.

This study aimed to investigate the heterogeneity of treatment effect for intra-aortic balloon pump (IABP) across various lactate trajectories in patients with acute myocardial infarction-related cardiogenic shock (AMICS) supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Retrospective data from the China Extracorporeal Life Support Registry included AMICS patients who received VA-ECMO. The latent class growth model was used to identify distinct lactate trajectories. The primary outcome was in-hospital mortality. Baseline characteristics and outcomes were compared across trajectory classes, and the heterogeneity of treatment effect for IABP was assessed. Among 1264 patients, three lactate trajectories were identified. Compared with Class 1, both Class 2 (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.54–2.67) and Class 3 (OR 3.99, 95% CI 2.77–5.78) had significantly higher in-hospital mortality. Moreover, heterogeneity of treatment effect across the classes was found. IABP use was associated with increased risks of in-hospital mortality and multiple complications (bleeding, renal, metabolic, and infection) in Class 1, whereas no associations were observed in Class 2 or Class 3, except for a higher risk of infection in Class 2. In summary, lactate trajectories can stratify mortality risk in AMICS patients receiving VA-ECMO support and reflect heterogeneous responses to IABP treatment.

Antibody–drug conjugates (ADCs) have emerged as a major therapeutic modality in oncology, enabling the targeted delivery of highly potent cytotoxic agents while expanding the therapeutic window in solid tumors. Recent clinical successes across breast, lung, and genitourinary cancers have highlighted that ADC efficacy is governed not only by target expression, but also by the integrated optimization of antibody engineering, linker chemistry, payload selection, and tumor-specific biology. In this review, we summarize the fundamental principles underpinning ADC design, including antibody format and Fc engineering, linker stability, payload classes, drug-to-antibody ratio optimization, and the bystander effect. We then discuss tumor antigen biology and target landscapes across solid tumors, with particular emphasis on how antigen density, heterogeneity, internalization kinetics, and intracellular trafficking shape clinical activity. Uro-oncological malignancies—especially urothelial carcinoma—are presented as a clinically advanced and instructive paradigm for ADC development. Experience from these tumors illustrates both the opportunities and limitations of ADC therapy, including mechanisms of response and resistance, biomarker-driven patient selection, rational combination strategies, and safety management in real-world practice. Finally, we provide a forward-looking perspective on next-generation ADC development, highlighting emerging conjugation technologies, bispecific and conditionally activated ADCs, strategies to overcome resistance, and evolving clinical trial designs. By integrating engineering principles with tumor biology and clinical execution, this review aims to offer a translational framework to guide the future development and implementation of ADCs across oncology.

The c-MYC oncogene, a critical driver of malignancies, is frequently associated with poor prognosis because it promotes unchecked cell proliferation and alters gene expression. Effective targeting of c-MYC using conventional therapeutic strategies has been difficult, largely because of its unstructured nature. In the present study, we identified a myc-binding nanobody named as M4 from a synthetic phage-display nanobody library. We conjugated M4 with a cell-penetrating peptide (CPP) to generate a molecule CPM4 and examined the effects and action mechanisms of CPM4 in inhibition of tumor cell growth in vitro and in vivo. CPM4 exhibited efficient nuclear localization, caused c-MYC reduction, and induced apoptosis in MYC-expressing cells. Hydrogen/deuterium exchange mass spectrometry revealed that CPM4 binds to the central PEST sequence (241–263 epitope) of c-MYC with high affinity. Further analysis revealed that CPM4 promotes c-MYC degradation via enhanced phosphorylation at Thr58, disrupts the c-MYC/MAX heterodimer, and downregulates c-MYC-targeted downstream genes. Xenograft studies further validated the therapeutic efficacy of CPM4, showing a significant reduction in tumor growth. These results underscore the therapeutic potential of CPM4 as an effective drug candidate for inhibiting c-MYC-driven tumor growth.

Chimeric antigen receptor T (CAR-T) cells have been used to treat patients with glioblastoma (GBM) in clinical trial settings by targeting GBM-associated antigens. However, the efficacy of these CAR-T cells remains limited mainly due to the heterogeneous expression of tumor antigen and their anergy in the tumor microenvironment (TME). Cytokine-inducible SH2-containing protein (CIS, encoded by the gene CISH) is a potent intracellular checkpoint inducing T-cell anergy. Here, we identified fibroblast activation protein alpha (FAPα) as a highly attractive target for CAR-T cell therapy against GBM based on its dual expression pattern (on tumor cells and perivascular cells) in GBM. A panel of nanobodies specific for FAPα was isolated, and FAPα-targeting CAR-T cells were developed using the isolated nanobody to verify their specific cytotoxicity to GBM cells. Furthermore, a non-viral circular single-stranded DNA (cssDNA)-based CRISPR/Cas9-targeted genome-editing (cssDNA/CRISPR/Cas9) technology was used to integrate CAR cassettes at the CISH locus to generate CISH-knockout (CISH-KO) CAR-T cells. The resulting CISH-KO-CAR-T cells exhibited robust proliferation and potent anti-GBM activity in vitro and in vivo. Thus, our results provide novel engineered CAR-T cells with enhanced efficacy against GBM.

L. Ji, Y. Ruan, M. Tong, et al., “circRNA-SORE/UBQLN1/GPX4 Mediates the Acquisition of Sorafenib Resistance in Hepatocellular Carcinoma Through Inhibition of Ferroptosis,” MedComm 6, no. 12 (2025): e70488.

In figure 4, the result shown in H was mistakenly used. We updated it with the correct result.

We apologize for this error.

Cerebral infarction, the pathological basis of ischemic stroke, remains a leading cause of mortality and long-term disability worldwide. Its clinical heterogeneity reflects the complex interplay among vascular pathology, metabolic failure, immune responses, and genetic susceptibility, posing persistent challenges to effective risk stratification and individualized therapy. This review provides an integrative overview of cerebral infarction from a precision medicine perspective, synthesizing advances across epidemiology, pathophysiology, diagnostics, and therapeutics to bridge the gap between mechanistic insight and clinical outcomes. We first summarize global epidemiological trends, highlighting persistent disparities and the shift toward understanding modifiable and emerging risk factors. We then critically examine the evolution of stroke classification from traditional systems (e.g., Trial of Org 10172 in Acute Stroke Treatment [TOAST]) toward phenotype-driven and molecularly informed frameworks. The core of the review delves into key pathophysiological mechanisms—including neurovascular unit dysfunction, energy metabolism disturbance, and regulated cell death pathways such as ferroptosis—and their implications for targeted intervention. We further appraise contemporary diagnostic advances, encompassing multimodal imaging, circulating biomarkers, and artificial intelligence-assisted tools, alongside current treatment strategies like reperfusion therapy and emerging neuroprotective approaches. Finally, we discuss how multiomics technologies and data-driven models are redefining stroke subtyping and guiding individualized management. By employing a mechanism–phenotype–decision framework, this review offers a coherent synthesis of the field, providing a roadmap to support the transition from empirical care toward precision-oriented management in cerebral infarction.

Type 1 diabetes (T1D) in children exhibits substantial heterogeneity in glycemic control, yet the biological mechanisms underlying this variation remain unclear. We aimed to explore endotype heterogeneity in youth with recent-onset T1D using unsupervised clustering based on multi-omics data, and to identify associated molecular signatures and underlying mechanisms. In a discovery cohort of 69 children and adolescents with recent-onset T1D, unsupervised clustering of fecal metagenomic profiles revealed two robust subgroups distinguished by hemoglobin A1c (HbA1c) levels. The High-HbA1c group was enriched in Bacteroidota, while the Low-HbA1c group was enriched in Firmicutes and certain Bacteroides species (Bacteroides ovatus, Bacteroides xylanisolvens, Bacteroides nordii, and Bacteroides cellulosilyticus). Metabolomics revealed significant enrichment of tryptophan-derived metabolites in the Low-HbA1c group. Bacteroides species signatures are positively correlated with tryptophan metabolite skatole. In an independent validation cohort, Bacteroides signatures discriminated individuals with good versus poor glycemic control (AUC = 0.854). Similar microbial patterns were observed in healthy children stratified by glycemic risk, indicating broader relevance of these signatures. Together, microbiome-based clustering identified glycemic control-related subtypes in T1D youth and suggested a potential role of Bacteroides and skatole in glycemic control. Mechanistic studies are warranted to confirm its role as a glycemic control-related endotype with distinct pathophysiology.

Hypertension and its associated complications, including vascular remodeling, pose a major burden on global public health. However, the role of Mas-related G protein-coupled receptor member D (MrgD) in hypertension remains incompletely understood. In this study, we observed upregulated MrgD expression in the arterial tissues of hypertensive patients and animal models. In Sprague-Dawley rats, MrgD overexpression elevated blood pressure (BP) and promoted mesenteric vascular remodeling, whereas MrgD knockdown in spontaneously hypertensive rats normalized BP and ameliorated vascular remodeling. Consistently, MrgD knockout mice exhibited resistance to angiotensin II (Ang II)-induced hypertension and vascular injury. Mechanistic investigations demonstrated that MrgD facilitated vascular remodeling in vascular smooth muscle cells (VSMCs) through the voltage-gated L-type Ca²⁺ channel (Cav1.2)-Ca²⁺/calmodulin-dependent protein kinase IIγ (CaMKIIγ) signaling axis. Co-immunoprecipitation coupled with mass spectrometry and in vitro functional assays confirmed that Ang II enhanced the interaction among MrgD, CaMKIIγ, and Cav1.2, thereby promoting VSMC phenotypic switch. Through artificial intelligence-driven screening combined with functional validation, we identified risperidone as a small-molecule inhibitor of MrgD that effectively attenuated hypertension and vascular remodeling. These findings established MrgD as a key contributor to the pathogenesis of hypertension and underscore its potential as a promising therapeutic target for hypertension and its associated vascular complications.

The functional significance of Chromosome 1 open reading frame 35 (C1orf35) in colorectal cancer (CRC) remains poorly characterized. This study investigates its oncogenic role and underlying mechanisms. We report that C1orf35 is frequently upregulated in CRC clinical specimens, and its elevated expression correlates strongly with advanced tumor stage and serves as an independent prognostic indicator for reduced overall survival. Functional assays, including experiments in patient-derived organoids, demonstrate that C1orf35 is essential for driving tumor cell proliferation, migration, and expansion. Mechanistically, we identify C1orf35 as an upstream activator of the transcription factor c-Myc. This activation triggers the transcriptional upregulation of the metabolic enzyme pyrroline-5-carboxylate reductase 2 (PYCR2), a key node in proline biosynthesis that facilitates tumor growth. Furthermore, we uncover a distinct, non-cell-autonomous function of C1orf35 in shaping the tumor immune microenvironment. Through c-Myc, C1orf35 impairs the cytotoxic function of tumor-infiltrating CD8⁺ T cells. This inverse spatial relationship between C1orf35 expression and CD8⁺ T-cell infiltration is validated by multiplex immunohistochemistry in human CRC tissues. Thus, our work defines C1orf35 as a dual-function oncoprotein that promotes CRC progression by coordinately enhancing tumor-intrinsic growth via the c-Myc/PYCR2 axis and fostering an immune-suppressive niche. These findings nominate C1orf35 as a promising multi-faceted therapeutic target and prognostic biomarker in CRC.

Cancer neuroscience has emerged as a paradigm-shifting discipline that reveals the active role of the nervous system in tumor development and progression. This review synthesizes current understanding of how bidirectional interactions between neurons and cancer cells influence tumorigenesis, metastasis, and therapy response. While earlier frameworks have established the fundamental mechanisms of nerve–tumor interactions, the present study proposes an expanded classification scheme that incorporates two additional mechanisms: perineural invasion as a unique metastatic pathway and neuro-microbic-oncology, which incorporates the gut–brain–immune axis into cancer biology. The remodeling of tumor microenvironment is structured around three principal mechanisms: electrochemical signaling, paracrine communication, and neuroimmune modulation. The contribution of these interactions to cancer-associated comorbidities, including pain, cachexia, and cognitive dysfunction, is highlighted, and their translational relevance is discussed in the context of emerging neurotherapeutic strategies. This review provides an integrated conceptual framework that connects neurobiology, oncology, and immunology, thereby informing the development of nerve-targeted therapeutic strategies with potential to improve clinical outcomes in cancer.

Neurofibromatosis type 1 (NF1) is characterized by the development of benign plexiform neurofibromas (PNFs). In 10%–15% of patients, these tumors undergo malignant transformation into aggressive malignant peripheral nerve sheath tumors (MPNSTs). The underlying mechanisms driving this malignant progression remain poorly understood, hindering the development of effective therapies. To address this gap, we performed single-cell RNA sequencing on nine PNF and five MPNST samples. Our analysis revealed tumor microenvironment remodeling during malignant progression, marked by a significant increase in immune cells. Within the macrophage compartment, we identified three distinct SPP1⁺ subpopulations. Among these, the SPP1⁺KYNU⁺ subset exhibited pronounced upregulation of genes related to tryptophan metabolism. This metabolically active macrophage population exhibited strong interaction with POSTN⁺ fibroblasts enriched in MPNSTs. Functional experiments found that this crosstalk promotes fibroblast activation and enhances migratory capacity. Furthermore, the metabolic reprogramming of SPP1⁺KYNU⁺ macrophages was associated with the establishment of an immunosuppressive microenvironment characterized by T cell dysfunction. Collectively, our findings define a central role for SPP1⁺KYNU⁺ macrophages in coordinating both stromal remodeling and immune suppression during MPNST progression. These results not only advance our understanding of NF1-associated tumorigenesis but also identify tryptophan metabolism as a promising therapeutic target and potential diagnostic biomarker for MPNSTs.

The immune microenvironment of invasive mucinous adenocarcinoma of the lung (IMA), a rare and heterogeneous subtype, remains poorly characterized, limiting insights into its potential response to immunotherapy. In this multicenter study, we systematically evaluated programmed cell death ligand 1 (PD-L1) expression (using tumor proportion score, TPS, and combined positive score, CPS) and cluster of differentiation 8-positive (CD8⁺) tumor-infiltrating lymphocyte (TIL) infiltration in the largest cohort to date of pathologically confirmed pure IMAs (n = 312), supported by single‑cell transcriptomic analysis. PD-L1 positivity was low (TPS≥1%: 9.0%; CPS≥1: 28.5%). While PD-L1 alone showed no prognostic significance, high CD8⁺ TIL percentage and density were independent, favorable prognostic factors for relapse-free survival, particularly in patients not receiving adjuvant therapy. By integrating TPS and CD8⁺ TIL percentage, we established a novel four-category immune phenotype classification that identified a distinct subgroup (Type IV: PD-L1⁺/CD8⁺) with significantly better outcomes. Preliminary analysis of 20 patients who received immune checkpoint inhibitors suggested that Type IV patients may derive greater clinical benefit. Single-cell RNA sequencing analyses revealed a paucity of effector CD8⁺ T cells in IMA. This work defines the unique immune landscape of IMA, introduces a clinically relevant immune phenotyping framework with prognostic and predictive potential, and provides a rationale for future immunotherapeutic strategies in this rare malignancy.

Spontaneous pregnancy loss (SPL) remains an important yet poorly understood pregnancy outcome. One-carbon metabolism (OCM) nutrients play an essential role in embryonic development, but their relationship with SPL remains unclear. In this prospective cohort of 11,033 couples and 2862 unpaired mothers, we assessed associations between preconception parental one-carbon metabolism (OCM) nutrients and SPL risk. We used generalized linear models to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for fathers, mothers, and the combined parental population, respectively. Each 100 ng/mL increase in paternal and maternal red blood cell (RBC) folate was associated with a 19% (aRR = 0.81; 95% CI, 0.73–0.90) and an 8% (aRR = 0.92; 0.85–0.98) lower SPL risk, respectively. The risk was reduced by 64% (aRR = 0.36; 0.16–0.79) when both parents achieved levels ≥ 400 ng/mL, compared to neither. Exploratory case–control analysis suggested associations of parental serum betaine with increased risk of SPL (β [standard error]: 0.09 [0.11] for fathers; 0.02 [0.08] for mothers) and inverse associations for taurine (−0.09 [0.11] and −0.03 [0.08], respectively). These findings highlight paternal and maternal preconception RBC folate, and imbalances in OCM metabolites are associated with an increased SPL risk, offering novel insights into SPL etiology and have public health implications.

The blood–brain barrier (BBB) is a highly selective and dynamic neurovascular interface essential for maintaining central nervous system homeostasis. This specialized barrier comprises brain microvascular endothelial cells interconnected by tight junctions, supported by pericytes and astrocytic end-feet within the neurovascular unit. While protecting the brain from circulating pathogens and toxins, the BBB presents formidable obstacles to drug delivery, restricting approximately 98% of small-molecule therapeutics and nearly all large biomolecules from reaching the brain parenchyma. BBB dysfunction is critically implicated in the pathogenesis and progression of numerous neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain tumors. This comprehensive review systematically examines the structural organization and functional characteristics of the BBB, elucidates its pathophysiological roles across major neurological diseases, and critically evaluates innovative drug delivery strategies designed to overcome this biological barrier. We analyze passive targeting approaches, active targeting mechanisms via receptor-mediated transcytosis, and stimuli-responsive systems including focused ultrasound and magnetic guidance. Additionally, we discuss multifunctional nanoplatforms, biomimetic cell membrane-coated delivery systems, current preclinical evidence, and clinical translation challenges. Finally, we propose future research directions and identify specific experimental pathways to accelerate the development of next-generation BBB-targeted therapeutics from preclinical promise to clinical application.

Single-cell and spatial omics have revolutionized biomedical research by enabling high-resolution molecular profiling across cells and tissues, thereby overcoming key limitations of bulk sequencing and revealing unprecedented cellular heterogeneity and spatial organization central to development, homeostasis, and disease. Specifically, advances in high-throughput, subcellular, and multiomics profiling are promoting the field toward deeper insights. In parallel, computational progress, including generative artificial intelligence (AI) and foundation models, is developing rapidly for manipulating multimodal multiomics data. These advancements have been applied to diverse diseases and biological systems, facilitating innovative biomedical findings. However, a significant gap persists between rapid methodological advances and their systematic application for deciphering human biology and pathology. This review synthesizes recent breakthroughs in single-cell and spatial technologies and surveys computational methods, including AI-driven approaches, foundation models, and multi-omics integration algorithms for both single-cell and spatial analyses. We then summarize representative applications across major human organ systems in health and disease, highlighting opportunities for biomarker discovery, therapeutic target identification, and precision medicine. Finally, we discuss current challenges and future directions for bridging technological innovation with robust biomedical discovery and translational impact. This review provides a vital guide for researchers in the field, offering critical insights for accelerating the translation of single-cell and spatial omics.

Diabetes mellitus poses a major global health burden and is intricately linked to cardiovascular complications, yet the spatial molecular landscape of diabetic vasculopathy remains poorly defined. Since thoracic and abdominal aortas differ in embryological origin and hemodynamic microenvironments, we applied laser-capture microdissection to map their spatial proteomes in health and diabetes, using a multidimensional framework across longitudinal (region) and transverse (disease) axes. This approach uncovered region-specific protein and pathway signatures obscured by conventional bulk analyses, highlighting spatial heterogeneity in transcriptional regulators and flow-sensitive proteins. We identified dipeptidase 1 (DPEP1), a membrane-bound zinc metalloprotease, as selectively upregulated in the diabetic thoracic aorta and inducible by diabetic conditions and shear stress. Mechanistically, laminar shear stress promoted glucocorticoid receptor (GR) nuclear translocation to drive a GR/DPEP1 axis, potentially explaining region-specific DPEP1 induction and its synergy with diabetic conditions. Functionally, chronic Dpep1 inhibition by cilastatin and endothelium-specific Dpep1 knockdown attenuated neutrophilic vascular inflammation and rescued endothelial dysfunction in diabetic mice. Furthermore, the corticosteroid dexamethasone activated the shear stress-responsive GR/DPEP1 axis in vivo, yet exerted time-dependent vascular effects—acutely dampening neutrophilic inflammation, but chronically worsening hyperglycemia and aggravating vascular dysfunction. These findings reveal spatially defined biomarkers and highlight DPEP1 as a therapeutic target in diabetic vasculopathy.

The ongoing evolution of SARS-CoV-2 and its immune-evading variants underscores an urgent requirement for broad-spectrum antiviral drugs. In this study, a series of lycorine derivatives was synthesized. This led to the identification of compound 7 as a promising antiviral candidate. Compound 7 exhibited potent inhibitory activity against SARS-CoV-2 and its variants, including Alpha, Beta, Delta, and Omicron, in vitro. The antiviral efficacy of compound 7 was then validated in vivo. Treatment with compound 7 significantly reduced viral loads and alleviated lung pathologies in SARS-CoV-2-infected hamsters. Mechanistically, compound 7 directly targeted the short isoform of the zinc-finger antiviral protein (ZAP-S) and bound to specific residues (E111, E115, and F549). This result was confirmed using cellular thermal shift assays, bio-layer interferometry, and mutagenesis studies. This interaction enhanced the ZAP-S stability and disrupted –1 programmed ribosomal frameshifting (–1PRF), a critical process for viral polyprotein synthesis. The antiviral activity of compound 7 was ZAP-S-dependent, as ZAP-S knockdown abolished its efficacy while overexpression enhanced it. These results established compound 7 as a novel antiviral candidate that can combat SARS-CoV-2 and its variants by targeting ZAP to inhibit –1PRF. This compound, therefore, represents a promising therapeutic strategy.

Acute lung injury (ALI) is characterized by a considerable mortality rate and currently lacks viable therapeutic strategies. Alveolar type II epithelial cells (AT2 cells) play a critical role in lung injury repair, potentially through activation of the Wnt/β-catenin signaling cascade, which may enhance regenerative ability of lung tissue. In this study, we developed a mini-catalytically inactive Cas13X (mini dCas13X)-based adenosine-to-inosine (A-to-I) RNA editing approach, designated as β-catenin T41 editing to treat alveolar type 2 cells (CARTEL), with the objective of alleviating lung damage in ALI. We found that CARTEL proficiently performed base editing on β-catenin, achieving a high A-to-I conversion rate with minimal off-target effects. Moreover, CARTEL significantly inhibited the degradation of β-catenin, amplified Wnt/β-catenin signaling activation and facilitated cellular proliferation. In a murine model of lipopolysaccharide (LPS)-induced ALI, a single adeno-associated virus (AAV)-mediated administration of CARTEL effectively and primarily transduced AT2 cells, resulting in attenuated lung injury, enhanced AT2 cell proliferation, and improved pulmonary function, with no detected long-term risks. Collectively, these findings revealed that CARTEL-mediated RNA editing represents a promising therapeutic strategy to counteract lung injury occurring in diverse settings.

Glioblastoma multiforme (GBM) is an aggressive, therapy-resistant brain tumor with limited treatment options. Epidermal growth factor receptor (EGFR) drives GBM pathogenesis. Here, we investigate ZYH005 (Z5), a brain-penetrant DNA intercalator with low systemic toxicity, as a novel therapeutic agent. Z5 potently inhibits the proliferation of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) in vitro and suppresses tumor growth in orthotopic GSCs-derived mouse models, significantly prolonging survival without apparent toxicity. Mechanistically, Z5 exerts potent anti-GBM activity through a dual mechanism: DNA intercalation-induced damage and targeted inhibition of EGFR. By specifically inhibiting EGFR at E762, Z5 not only enhances DNA damage by suppressing the DNA damage response in the nucleus but also disrupts the interaction between nuclear EGFR and WEE1, leading to impaired WEE1/CDC2 signaling and G2/M checkpoint failure. Extranuclearly, Z5 further enhances its anti-GBM efficacy by inhibiting the canonical EGFR downstream pathways, mTOR, and ERK. These combined actions lead to cell cycle arrest and mitotic catastrophe. Our findings establish Z5 as a promising clinical candidate for classical GBM, employing a unique dual mechanism that overcomes EGFR-targeted and DNA-damaging therapy limitations by synergistically targeting DNA and EGFR with high efficacy, advancing understanding of EGFR–WEE1 biology, and supporting clinical development.

This study aimed to identify blood pressure-associated metabolites and explore their underlying pathways using multiomics data from 1188 Chinese participants. Serum metabolite levels were profiled using untargeted and widely targeted metabolomic technologies. The associations of metabolites as well as ratios with blood pressure were assessed using generalized linear models (GLM). Targeted metabolomics was used to replicate a subset of metabolites. Genome-wide association studies (GWAS) were performed on all metabolites identified. Potential causality was examined using two-sample Mendelian randomization (MR) analyses, with partial validation against GWAS results from an independent cohort. This study identified 10 blood pressure-associated metabolites supported by GLM and MR analyses. Cortisol demonstrated the strongest association with blood pressure, with l-glutamic acid and its ratios identified as key drivers. Multiomics integration revealed that a genetic variant near the omega-3 metabolism genes (FADS1/FADS2) may influence blood pressure regulation by modulating prostaglandin E3 levels. Mediation analysis indicated that l-glutamic acid statistically mediated 12.16–31.53% of the effect of lifestyle factors on blood pressure. These findings enhance our understanding of metabolic mechanisms underlying hypertension and highlight potential biomarkers and therapeutic targets for further investigation.

Neoadjuvant immunotherapy-based combination holds promises in reducing surgical risk and improving survival for renal cell carcinoma (RCC) with venous tumor thrombus (VTT). However, its role in RCC–VTT has been less explored. To evaluate the efficacy and safety of neoadjuvant toripalimab plus axitinib in nonmetastatic RCC–VTT, we conducted a combined analysis of two Phase II trials with similar design. Thirty-four patients with nonmetastatic clear cell RCC (ccRCC) and Mayo Level 0–IV VTT were enrolled. Toripalimab plus axitinib was administered for up to 12 weeks before surgery. The primary endpoint was objective response rate (ORR). In this study, the ORR and disease control rates were 41% (14 out of 34) and 97% (33 out of 34), respectively. 47% (16 out of 34) patients experienced a reduction in VTT levels. Grade 3 treatment-related adverse events (TRAEs) occurred in 24% (eight out of 34) patients, and no Grade 4 or 5 TRAEs were observed. Thirty patients were eligible for surgery, and the surgical strategy was simplified in 53% (16 out of 30) patients. One-year disease-free survival and overall survival were 76.7% (95% CI, 59.1–88.2%) and 91.2% (95% CI, 77.0–97.0%), respectively. Multiomics analysis revealed the nonresponder group exhibited significant tumor heterogeneity and a stroma-characterized tumor microenvironment. In conclusion, neoadjuvant toripalimab plus axitinib was clinically active and safe in patients with nonmetastatic ccRCC–VTT.

Immune checkpoint inhibitors (ICIs) universally enhance antitumor immunity but endanger a subgroup of patients by triggering immune-related adverse events (irAEs). We profiled the expressions of 41 proteins on peripheral blood mononuclear cells (PBMCs) prior the initiation of immunotherapy. CXCR3 and CCR6 expressions were significantly decreased in PBMC subpopulations from patient with irAEs but not from those who responded to PD-1 inhibitors. The expression of CCR6 in a NK cell subpopulation serves exclusively as a biomarker to differentiate patients who developed irAEs. Interestingly, circulating ligands of CXCR3, including CXCL9, CXCL10, and CXCL11, were significantly increased in patients who later developed irAEs after PD-1 inhibitor treatment. The decreases of CXCR3 in three T cell subpopulations and decreases of CCR6 in a NK cell subpopulation were further validated in two independent external cohorts. Moreover, multiple proteins in PBMCs, distinct from the irAE-predicting biomarkers, exhibited differential expression levels corresponding to the differential responses to the PD-1 inhibitors. Via multiple independent cohorts, our study revealed crucial roles of CXCR3 and CCR6 in PD-1-induced irAEs, provided potential circulating biomarkers associated with toxicity and responses of PD-1 inhibitors and further sculptured the landscape of immune cell heterogeneity via focusing on PBMC subpopulations.

The major challenge in the clinical treatment of gastrointestinal mucosal injury caused by high-altitude hypoxic environments lies in its unclear underlying mechanisms. In the previous study, we found that hypoxia-induced gastric and small intestinal damage was mainly attributable to ferroptosis mediated by hypoxia-inducible factor-α (HIF-α; mainly HIF-1α and HIF-2α). Both plant exosome-like nanoparticles and Aquilaria malaccensis Lam. have been reported to have antioxidant properties. In the present study, orally delivered A. malaccensis Lam. exosome-like nanoparticles (AELNs) reduced HIF-1α expression and alleviated gastric and small intestinal mucosal ferroptosis induced by hypoxia. We analyzed the compositions of AELNs and hypothesized that ipriflavone was the effector component, as it showed the highest abundance of metabolites. Subsequent experiments demonstrated that ipriflavone downregulated polyunsaturated fatty acid-phospholipids, NADPH oxidase 4 (NOX4), and arachidonate 5-lipoxygenase (ALOX5) by inhibiting HIF-α, consequently alleviating hypoxia-induced gastric and small intestinal mucosal ferroptosis. Ipriflavone was found to inhibit HIF-α by targeting prolyl hydroxylase domain protein 2 (PHD2) to induce it to hydroxylate HIF-α. This study highlights that ipriflavone, a potent HIF-α inhibitor, significantly ameliorates the gastric and small intestinal mucosal damage caused by hypoxia and has promise in clinical applications for treating disorders characterized by high levels of HIF-α.

The positive transcription elongation factor b (P-TEFb) complex, composed of CDK9 and cyclin T isoforms (T1, T2a and T2b), is critical for gene transcription, positioning CDK9 as a very promising oncology target. However, the development of selective and clinically effective small-molecule CDK9 inhibitors has proven challenging. To overcome this limitation, we designed a series of highly efficient and selective P-TEFb degraders by conjugating the CDK9 inhibitor SNS032 with the mouse double minute 2 (MDM2) ligand RG7388. Our lead compound, 13 (dCDK9-010), recruits the MDM2 E3 ligase to induce proteasome-dependent degradation of CDK9 and all cyclin T isoforms across diverse cancer models. dCDK9-010 potently inhibits RNA polymerase II carboxy-terminal repeat domain phosphorylation and blocks MDM2-mediated p53 degradation, resulting in concurrent p53 pathway activation. This dual mechanism drives selective cytotoxicity in TP53 wild-type cancer cells, sparing TP53-mutant or nonmalignant cells. In murine xenograft models of lung cancer and Ewing sarcoma, intravenous dCDK9-010 administration significantly inhibited tumor growth while demonstrating an excellent safety profile. Collectively, this study establishes dCDK9-010 as a first-in-class, selective MDM2-recruiting P-TEFb degrader. By enabling the elimination of the entire P-TEFb complex, this MDM2-recruiting degradation strategy expands the toolkit for targeting CDK9 and represents a promising new therapeutic paradigm for TP53 wild-type cancers.

J. Zhang, H. Gong, T. Zhao, et al., “AMPK-Upregulated microRNA-708 Plays as a Suppressor of Cellular Senescence and Aging Via Downregulating Disabled-2 and mTORC1 Activation,” MedComm 5, no. 3 (2024): e475, https://doi.org/10.1002/mco2.475.

In Paragraph 5 of the “Acknowledgments” section, the text “Chongqing Postdoctoral Science Foundation Project (Grant Nos. 2023NSCQ-BHX0074 to Jian Zhang)” was incorrect.

This should have read: “the Postdoctoral Project of Chongqing Natural Science Foundation (Grant Nos. CSTB2023NSCQ-BHX0092 to Jian Zhang)”

We apologize for this error.

Oncolytic virotherapy is an emerging cancer immunotherapy that combines selective tumor cell lysis with activation of systemic antitumor immunity. Various DNA- and RNA-based oncolytic viruses (OVs) have demonstrated favorable safety profiles and therapeutic activity across different malignancies. Despite these advancements, clinical efficacy remains inconsistent because of several biological barriers, including rapid immune clearance, insufficient tumor targeting, limited intratumoral spread, and the immunosuppressive tumor microenvironment (TME). In this review, we examine the key mechanisms of OV infection, tumor selectivity, and virus-induced antitumor immune responses. It also explores the factors that limit therapeutic efficacy, particularly host antiviral immunity, structural barriers within solid tumors, and the immunosuppressive networks in the TME. To address these challenges, a range of strategies have been developed, with a focus on optimizing viral delivery. Current approaches, such as cell-based carriers, extracellular vesicle-mediated transport, and nanomaterial-assisted delivery systems, aim to enhance tumor targeting, protect viral integrity, and improve intratumoral distribution. Additionally, combination therapies designed to enhance antitumor immunity and reshape the TME are outlined, including immune checkpoint blockade, chemoradiotherapy, and metabolic modulation. Collectively, these advancements transform OVs from standalone cytolytic agents into adaptable immunotherapeutic platforms, with their effectiveness determined by the delivery method, microenvironmental conditions, and therapeutic integration.

Porcine islet xenotransplantation is effective for severe diabetes; however, preclinical studies are essential. In this study, we evaluated the suitability of the Japanese macaque as a recipient model for islet xenotransplantation, including identifying the preferred method to induce diabetes. The safety and stability of the following four models to induce diabetes were assessed: Model 1: pancreatectomy, Model 2: pancreatectomy with low-dose streptozotocin (STZ), Model 3: single-injection of STZ, and Model 4: consecutive administrations of low-dose STZ. Diabetes was induced in all four models. The blood glucose level after induction of diabetes was 225.32 ± 46.49 mg/dL in Model 1, 209.64 ± 64.36 mg/dL in Model 2, 175.51 ± 45.18 mg/dL in Model 3, and 139.22 ± 6.31 mg/dL in Model 4. Regarding safety, Models 1 and 2 involved invasive surgery with postoperative concerns. Model 3 induced diabetes in the Japanese macaques; however, the preferable dose of STZ was individual dependent. Among the models, Model 4 was preferable regarding safety and stability. Finally, we performed porcine islet xenotransplantation in a diabetic monkey in Model 4 and evaluated the therapeutic effects of this treatment. In conclusion, the Japanese macaque might be a possible recipient model for porcine islet xenotransplantation.

Osteoarthritis (OA) is the most common chronic joint disorder and a major cause of disability worldwide. Once regarded as a consequence of cartilage wear, OA is now recognized as a complex whole-joint disease involving coordinated pathological changes in articular cartilage, synovium, and subchondral bone. Disease progression is driven by chronic low-grade inflammation, metabolic dysregulation, oxidative stress, and abnormal cellular responses to mechanical stress. These processes are mediated by interconnected signaling networks that regulate inflammatory responses, extracellular matrix (ECM) metabolism, and tissue remodeling. Epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs, are increasingly recognized as regulators of OA-related gene expression. However, how signaling networks integrate with epigenetic regulation, particularly histone methylation, remains incompletely understood. In this review, we summarize the epidemiological burden and major risk factors of OA, describe pathological remodeling across joint tissues, and discuss key signaling pathways involved in OA pathogenesis before outlining epigenetic mechanisms. We also highlight the role of histone methylation in inflammation, metabolic imbalance, and tissue remodeling, and summarize current nonpharmacological, pharmacological, injectable, and surgical treatment strategies. Together, this review provides an integrated overview of the epidemiology, pathogenesis, and treatment of OA.

The histone-lysine N-methyltransferase (KMT2) family is a central epigenetic regulator whose dysfunction drives diverse human diseases through distinct molecular mechanisms. In acute leukemias, KMT2A rearrangements aberrantly recruit transcriptional cofactors, activating oncogenic gene programs; in solid tumors, loss-of-function mutations in KMT2C/D disrupt enhancer-mediated regulatory networks, compromising cellular identity and genome stability; in neurodevelopmental disorders, germline haploinsufficiency of KMT2A/B/D impairs developmental epigenetic programming. Despite increasingly comprehensive understanding of the pathogenic mechanisms involving KMT2 family members, a unified framework translating these molecular insights into effective, subtype-specific therapeutic strategies has been lacking. This review comprehensively deconstructs these pathogenic pathways and explores how mechanistic insights are being translated into novel therapeutic strategies, including direct targeting of oncogenic transcriptional complexes, exploiting vulnerabilities from tumor suppressor loss, and modulating the tumor immune microenvironment. We systematically synthesize recent clinical advances, from small-molecule inhibitors against protein–protein interactions (e.g., menin–KMT2A), to targeted degraders (PROTACs), epigenetic readers/writers inhibitors (e.g., BET, LSD1, DOT1L), and rational combination regimens with chemotherapy or immunotherapy. By integrating the biological characteristics of KMT2 with translational medicine and clinical evidence, this study provides a framework for advancing precision medicine approaches based on the molecular subtypes driven by KMT2.

Posttranslational modifications (PTMs) act as rapid, reversible switches that reshape protein activity, stability, and interactome, thereby governing virtually every physiological cue from signal transduction to epigenetic memory. Mass spectrometry-based proteomics has considerably extended our knowledge about the occurrence and dynamics of PTMs. Pinpointing disease- or physiology-specific PTM sites remains an open challenge. As a biological process with well-defined stage-specific markers and a precise endpoint, erythropoiesis is orchestrated by the complex interplay of multiple PTM-regulatory networks, making it an ideal model for dissecting the spatiotemporal dynamics, quantitative thresholds, and crosstalk of PTMs. This review delineates the applications, detection, and prediction technologies of PTMs, with an emphasis on the mechanisms of phosphorylation, ubiquitination, methylation, SUMOylation, glycosylation, and acetylation in both physiological and pathological processes. Dissecting PTM circuitry driving erythroid specification and maturation, we show how its perturbation triggers disease, clarifying PTM roles. Additionally, we have investigated the progress made in the clinical translation and drug development of the PTMs field, emphasizing the potential of PTMs in the field of precision medicine as well as the existing challenges. This review aims to provide new insights and perspectives for the study of PTMs.

Chest radiographs (CXRs) may encode prognostic signals beyond pulmonary nodule detection. We developed LungProNet, a multimodal deep-learning (DL) model that fuses CXR features with four epidemiologic variables (age, sex, smoking history, and family history) for pulmonary nodule detection as the primary task, with secondary validation for all-cause and cause-specific mortality prediction. LungProNet was trained and internally validated on Tianjin Lung Cancer Imaging Dataset (TLCID) (70/30; n = 2852/1227) and externally validated on ChestDR (n = 4848), with stratified analyses across epidemiologic strata. Discrimination was quantified by area under the curve (AUC) (95% confidence intervals), with accuracy, sensitivity, and specificity reported, and results were benchmarked against contemporary machine learning/DL baselines. The pretrained multimodal encoder was transferred without fine-tuning to the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) (n = 24,697); its fused embeddings were used as covariates in Cox proportional-hazards models, and time-dependent AUCs were evaluated at 1–12 years. For nodule detection, AUCs were 0.979 (0.975–0.982) in TLCID and 0.849 (0.835–0.862) in ChestDR; the TLCID stratified model reached 0.990 (0.984–0.994). In PLCO, AUCs were 0.925 (0.892–0.952) for all-cause mortality and 0.939–0.985 for cardiac-, lung cancer-, and Chronic Obstructive Pulmonary Disease (COPD)-cause mortality, with robust subgroup performance. These results support CXR-based nodule flagging within screening workflows and suggest secondary opportunistic risk stratification potential.

Risk stratification in patients with angina and nonobstructive coronary arteries (ANOCA) remains suboptimal. Coronary flow velocity reserve (CFVR) is prognostic but susceptible to hemodynamic variability; we evaluated whether hyperemic coronary flow velocity (hCFV) improves risk prediction. We analyzed 246 consecutively enrolled ANOCA patients and an independent validation cohort (n = 135). Transthoracic Doppler of the mid-distal LAD quantified CFVR and hCFV. The primary end point was major adverse cardiovascular events (MACE). During a median follow-up of 28.8 months, 27 patients (10.9%) experienced MACE. Both CFVR and hCFV were significantly associated with MACE. Among patients with CFVR < 2.5, hCFV ≤ 0.44 m/s independently predicted MACE (adjusted HR 6.6, p = 0.001). A combined CFVR-hCFV scheme yielded graded risk of MACE (Group A: CFVR ≥ 2.5; Group B: CFVR < 2.5 with hCFV > 0.44 m/s; Group C: CFVR < 2.5 with hCFV ≤ 0.44 m/s), with Group C exhibiting the highest risk of MACE (35.5% vs. 6.3%, 10.5%, p < 0.01). Adding reduced hCFV to a model including clinical risk factors and CFVR improved prediction (IDI 0.05, p = 0.011; NRI 0.23, p = 0.0023) and was confirmed in the validation cohort. Reduced hCFV provides incremental prognostic value beyond CFVR and offers a practical approach to identify high-risk ANOCA patients.

Breast cancer (BC) is a clinically heterogeneous malignancy and a leading cause of cancer-related mortality in women worldwide. It is classified into hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative (TNBC) subtypes based on molecular biomarkers. This heterogeneity drives distinct disease progression and treatment responses, making subtype-specific precision therapy indispensable for improving patient outcomes. While estrogen receptor (ER)-targeting agents and anti-HER2 therapies have achieved notable successes, critical challenges remain, including drug resistance, inadequate biomarkers, and limited therapeutic targets for TNBC. This review comprehensively summarizes recent advances in targeted therapies for major BC subtypes: endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for HR-positive BC; novel antibody‒drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and tyrosine kinase inhibitors (TKIs) for HER2-positive BC; and trophoblast cell-surface antigen 2 (Trop-2) ADCs, immunotherapies, and poly-ADP-ribose polymerase (PARP) inhibitors for TNBC. It also discusses cross-subtype therapeutic platforms (ADCs, PI3K/AKT/mTOR pathway) and emerging modalities (chimeric antigen receptor [CAR] T-cell therapy, proteolysis-targeting chimeras [PROTACs]). By analyzing successes, challenges, and translational potential, this review provides a clear framework for clinicians and researchers, advancing personalized treatment optimization and addressing unmet clinical needs in BC precision oncology.

Epilepsy is a prevalent and often severe neurological disorder with significant economic and societal impacts. Despite adequate trials with two or more antiseizure medications (ASMs), approximately one-third of patients continue to experience drug-resistant epilepsy. Surgery remains the most effective treatment for patients with drug-resistant focal epilepsy, yet it may be underutilized. Given the unsatisfactory clinical outcomes, it is imperative to investigate the molecular pathogenesis of epilepsy and to develop novel therapeutic strategies. This review systematically outlines the advances in understanding the etiology and molecular pathogenesis of epilepsy. These advances have identified diverse therapeutic targets, stimulating the development of emerging therapies, including novel ASM, minimally invasive surgery, neurostimulation, focused ultrasound, nanomedicine, gamma-aminobutyric acid (GABA)ergic cell therapy, and gene therapy. Additionally, the review comprehensively evaluates emerging therapies for epilepsy from different perspectives by integrating findings from both preclinical and clinical studies. These innovative approaches offer the potential for long-term seizure control. A great deal of future research is still needed to overcome current shortcomings. This work provides a cohesive framework that bridges molecular mechanisms with therapeutic applications. Such efforts may provide novel ideas and optimizing approaches in the field, ultimately advancing the precision and effectiveness of epilepsy treatments in the future.

We aimed to evaluate associations of chronotype, genetic risk, and lifestyle with depression and anxiety. A total of 242,391 participants without anxiety and depression at baseline in UK Biobank were included. During a total of 3,393,260.1 and 1,371,872.8 person-years follow-up, we found 11,824 (4.88%) incident depression and 10,051 (4.15%) incident anxiety cases, respectively. Compared with definite morning group, individuals with intermediate (HR = 1.09, 95% CI = 1.04‒1.13) and definite evening chronotype (HR = 1.45, 95% CI = 1.36‒1.55) have higher risks of depression, and individuals with definite evening chronotype (HR = 1.27, 95% CI = 1.18‒1.37) have a higher risk of anxiety. We found joint association between chronotype and genetic risk, those with high genetic risk and definite evening chronotype had the highest risk of depression (HR = 2.01, 95% CI = 1.81‒2.23) and anxiety (HR = 1.40, 95% CI = 1.24‒1.58). We also found joint association between chronotype and lifestyle, those with least healthy lifestyle and definite evening chronotype had the highest risk of depression (HR = 1.99, 95% CI = 1.65‒2.40) and anxiety (HR = 1.69, 95% CI = 1.36‒2.10). Individuals with evening chronotype are associated with higher risks of depression and anxiety.

Currently, patients with advanced-stage or refractory human papillomavirus (HPV)-associated malignancies have few therapeutic options. Despite therapeutic HPV vaccines having been investigated, the lack of appreciable efficacy highlights the urgent need to develop more effective strategies. Here, we developed an immuno-oncotherapy for HPV-induced tumors based on an adenoviral (Ad)-vectored therapeutic vaccine that contains concatemeric T cell epitopes, and evaluated oncolytic viruses (OV) as potential approach to enhance vaccine efficacy. We observed that the therapeutic vaccine encoding the HPV E7 oncoprotein epitope (Ad-E7P) significantly inhibited tumor growth in HPV-induced murine models by inducing systemic antitumor CD8+T cell responses and promoting the formation of tertiary lymphoid structures in peritumoral regions. We then evaluated the potential of combining the vaccine with an interleukin-12 (IL-12)–armed oncolytic herpesvirus (SKV-012) in preclinical models. The combination therapy elicited potent antitumor responses by inducing antigen-specific T-cell expansion, remodeling the tumor microenvironment, and generating immune memory, which led to tumor clearance. Overall, these findings support that the vaccine synergizes with the OV as an effective approach to enhance antitumor immunity in HPV-associated malignancies.

Neurological and psychiatric disorders, arising from disruptions in neural circuitry, pose a major and growing challenge to global healthcare systems. Brain–computer interface (BCI) technology has emerged as a promising approach, enabling direct communication between the brain and external devices. By facilitating bidirectional interaction with the nervous system, BCIs open new avenues for both diagnosis and treatment. In this review, we examine recent advances in recording and stimulation technologies within the BCI framework and evaluate their therapeutic potential across major neuropsychiatric disorders. We focus particularly on post-stroke motor rehabilitation as a representative paradigm, providing detailed analysis of the mechanisms, clinical evidence, and future prospects of endovascular BCI, BCI-integrated epidural spinal cord stimulation, and BCI-driven deep brain stimulation. We further extend the discussion to movement disorders such as Parkinson's disease and epilepsy, as well as cognitive and psychiatric conditions including Alzheimer's disease and depression, highlighting how BCI-based approaches enable symptom detection and closed-loop neuromodulation. Additionally, we address ethical and societal considerations accompanying clinical translation of these advanced neurotechnologies. By integrating current evidence, this review highlights a paradigm shift toward more active, precise, and personalized neural rehabilitation enabled by BCI systems, while outlining key challenges and future directions for research and clinical application.

J. Zhang, Y. Song, J.-H. Koo, et al., "HSD17B7 Counters Bone Loss in Estrogen Deficiency via Estrogen Receptor Stabilization and Mediates the Effect of Raloxifene," MedComm 7, no. 2 (2026): e70623. https://doi.org/10.1002/mco2.70623.

The author name was published as:

Jeong-Hyun Koo

The correct author name is:

Jeung-Hyun Koo

We apologize for this error.

Organoids are innovative three-dimensional (3D) cellular constructs, offering a unique platform to replicate the architectural and functional complexity of organs and tissues. In oncology, the tumor microenvironment (TME) dictates tumor evolution and therapeutic resistance. Consequently, therapies targeting TME components have emerged as a burgeoning frontier in cancer treatment. However, accurately recapitulating the dynamic, multicellular crosstalk of TME remains a significant hurdle for clinical translation. This review encapsulates the spectrum of current organoid coculture methodologies, ranging from direct coculture and air–liquid interface to advanced microfluidics and 3D bioprinting. These models not only deepen our understanding of the fundamental mechanisms at play in cancer but also evaluate emerging therapeutic modalities, such as antibody–drug conjugates and immunotherapy. By closely mimicking the in vivo tumor milieu, organoid cocultures enhance our ability to predict therapeutic outcomes and pave the way for the development of precision medicine approaches, thereby propelling forward the frontiers of oncology. This review aims to provide a comprehensive overview of organoid coculture models, spanning from construction methodologies to clinical applications. We envision this work serving as a definitive guide for the field, ultimately accelerating the transition from theoretical research to clinical practice.