In the global response to the current mpox epidemic, understanding immune memory to the vaccinia virus and cross-immunity to the mpox virus (MPXV) among people living with HIV (PLWH) is critical. Blood samples were collected from PLWH born between 1949 and 2002 without MPXV infection, as well as from sex- and age-matched healthy donors (HD). Note that 62% and 56% of vaccinated PLWH born before 1980 had antibodies against the vaccinia virus Tiantan (VTT) strain and MPXV, respectively, though these seropositivity rates were lower than in HD (84% vs. 80%). Neutralizing antibodies were detected in 9% of PLWH, compared to 32% in HD. Notably, in PLWH with CD4 T-cell counts below 500 cells/mm³, VTT-IgG and MPXV-IgG titers, as well as VTT-specific memory B cells, were significantly reduced. In PLWH with CD4 T-cell counts below 350 cells/mm³, CD4⁺ memory T-cell responses were diminished, particularly in IFN-γ and TNF-α responses. In contrast, CD8⁺ T-cell responses to MPXV were comparable in PLWH regardless of CD4 T-cell counts. These findings highlight the diminished humoral and CD4⁺ T-cell responses in PLWH, particularly in those with lower CD4 T-cell counts, and underscore the necessity for targeted vaccination strategies in this population.

Lupus nephritis (LN) is one of the most severe manifestation of systemic lupus erythematosus (SLE). However, reliable tools for predicting LN risk remain limited. In this multicenter prospective cohort study, we developed, validated, and refined a risk stratification model for new-onset LN. A total of 2441 SLE patients without baseline renal involvement were consecutively enrolled from the Chinese SLE Treatment and Research (CSTAR) registry, with 215 (8.8%) developed LN in a median follow-up time of 3.5 years. A combination of clinical predictors, age < 30 years, absence of arthritis, serositis, hypocomplementemia, and positive anti-double-stranded DNA antibodies identified a clinical high-risk group (n = 537, 22.0%) with a 3-year LN incidence of 18.1%. The model was externally validated in 451 patients, with 50 developed LN in a median follow-up time of 3.4 years. In these patients, a genetic risk score (GRS) derived from 112 SLE-associated loci was found to be independently associated with LN (HR = 3.19, 95% CI, 1.83–5.55, p = 4.36 × 10⁻⁵). Among clinically low-risk individuals, those in the highest GRS quartiles (81/451, 18.0%) showed elevated 3-year LN incidence (15.5% vs. 1.4%). New-onset LN may be predicted using a combination of clinical risk factors, and integrating GRS further improves risk stratification, enabling early identification of high-risk patients.

Chronic obstructive pulmonary disease (COPD) associates with increased lung cancer incidence and shares genetic susceptibility, yet its independent causal role and driver mechanisms are poorly understood. We integrated data from the National Health and Nutrition Examination Survey (NHANES) cohort with genome-wide association studies (GWAS) summary statistics and Mendelian randomization analyses to map genetic correlations and infer causality between COPD phenotypes and lung cancer. Post-GWAS methods—including transcriptome-wide association study, colocalization, partitioned heritability via heritability estimation from summary statistics (ρ-HESS), and cross-phenotype association (CPASSOC)—identified shared susceptibility loci, highlighting IREB2 and CD27⁺ B cells as potential mediators. Elevated IREB2 expression correlated with accelerated lung-function decline in COPD but predicted improved prognosis in lung cancer B cells, whereas higher CD27⁺ B cell levels in COPD were associated with protumorigenic activity. Single-cell transcriptomic analysis and in vitro knockdown experiments confirmed IREB2's role in modulating B-cell activation and apoptosis pathways within tumors. These results support COPD as an independent lung cancer risk factor and implicate IREB2 and CD27⁺ B cells in COPD-to-cancer progression, laying groundwork for early detection and targeted intervention in high-risk individuals.

This multicenter retrospective study analyzed data from 1266 patients with advanced non–small cell lung cancer (NSCLC) across five leading hospitals in China. The aim was to evaluate survival outcomes and safety profiles of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The main outcomes included overall survival (OS) and progression-free survival (PFS), while the secondary endpoint was adverse events. Kaplan–Meier survival analysis, univariate and multivariate Cox regression modeling, and propensity score matching (PSM) analyses were performed to compare the real-world efficacies of PD-1 and PD-L1. Patients receiving PD-1 inhibitors had significantly longer median OS compared with those treated with PD-L1 inhibitors (28.2 versus [vs.] 24.6 months; hazard ratio [HR] 0.74 [95% confidence interval (CI) 0.59–0.93]; p = 0.0099), with consistent effects after PSM analysis (HR 0.70 [95% CI 0.12–0.91]; p = 0.005) and multivariable, adjusted Cox regression model with HR of 0.74 ([95% CI 0.59–0.93]; p = 0.01). Further analysis indicated that body mass index ≥ 24 kg/m² (HR 0.72 [95% CI 0.75–0.93]; p = 0.014) and history of hypertension (HR 1.35 [95% CI 1.01–1.79]; p = 0.037) may interfere with the therapeutic effects of PD-1 with comparable safety profiles, which renewed personalized immunotherapy options for NSCLC patients in clinical settings.

Lung cancer remains a leading cause of cancer-related mortality worldwide, with metastasis leading to a poor prognosis. While advances in primary tumor management have improved survival, disease dissemination to distant organs, particularly the liver, bone, and brain, represents an unresolved therapeutic challenge. Metastasis is governed by complex interactions between tumor cells and the microenvironment, including immune evasion, angiogenesis, and organotropism. Current therapies often fail to address site-specific molecular vulnerabilities or overcome physiological barriers such as the blood–brain barrier (BBB). A systematic review integrating clinical and mechanistic insights is urgently needed to guide translational efforts. This review synthesizes evidence on lung cancer metastases to three critical sites: liver metastases, where immunosuppressive niches and delayed diagnosis limit outcomes, and we emphasize the role of immune checkpoint inhibitors and liquid biopsies; bone metastases, characterized by osteolytic/osteoblastic lesions, which require biomarker-driven therapies and multimodal pain management; and brain metastases, where BBB penetration and heterogeneity demand tailored approaches. By dissecting organ-specific mechanisms, including circulating tumor cells, premetastatic niche formation, and metabolic reprogramming, this work highlights actionable targets for precision medicine. This review advocates for patient stratification and combination therapies to improve survival, offering a roadmap for future research on metastatic lung cancer.

Radiation has been wildly used in clinics for disease therapy over a century. However, the side effects associated with radiotherapy are often substantial and multifaceted, underscoring the need for effective management of radiation-induced injuries. Additionally, with the growing reliance on nuclear technology, concerns about accidental exposures have intensified. Radiation-induced biological effects represent a highly complex process that impacts multiple physiological activities within organisms. Ongoing research aims to elucidate the underlying molecular mechanisms and to develop reliable methods for radiation dose estimation—both for emergency scenarios and therapeutic applications. This review provides a systematic overview of the biological effects of ionizing radiation, covering DNA damage and repair pathways, cellular senescence, and diverse modes of cell death. It also offers an in-depth analysis of recent advances in radiation biodosimetry and the application of radiation in cancer therapy, along with insights into future research directions. By integrating mechanistic knowledge with practical applications, this review aims to support the optimization of radiation-based strategies, enhance public health preparedness, and inspire continued innovation in the field.

Ovarian aging is a fundamental process in female reproductive biology with broad implications for overall health and aging. As global populations age, understanding its mechanisms and systemic effects has gained urgent clinical relevance. The ovary, beyond its reproductive role, is increasingly recognized as a regulator of systemic aging due to the widespread presence of estrogen receptors. Declining ovarian function accelerates not only reproductive senescence but also contributes to age-related disorders including osteoporosis, neurodegenerative diseases, and cardiovascular conditions. However, research on ovarian aging remains fragmented, lacking integrative analysis. This review synthesizes recent advances in the cellular and molecular mechanisms underpinning ovarian aging, such as genomic instability, metabolic and oxidative stress, and microenvironmental alterations. It further discusses how ovarian decline influences systemic aging pathways and disease susceptibility and evaluates emerging therapeutic strategies such as antioxidant interventions, stem cell therapy, and ovarian tissue transplantation. By providing a comprehensive overview of ovarian aging from mechanisms to interventions, this review aims to bridge existing knowledge gaps and inspire future research toward improving women's healthspan and quality of life.

Protein arginine methyltransferase 1 (PRMT1) serves as a critical epigenetic modulator involved in a wide range of physiological and pathological processes. Previous studies have established its fundamental roles in essential cellular mechanisms such as DNA repair, transcriptional regulation, and signal transduction. Dysregulation of PRMT1 has been further associated with the pathogenesis of various diseases, including cancer, metabolic disorders, and immune dysfunction. However, a systematic synthesis of the multifaceted functions of PRMT1 across these diverse pathological contexts remains lacking. This review seeks to address this gap by comprehensively examining the molecular mechanisms, biological functions, and context-dependent roles of PRMT1. We integrate recent advances spanning multiple disease domains, with a particular focus on cancer, chronic liver diseases, cardiovascular disorders, neurodegenerative conditions, and immune-related pathologies. In addition, we elucidate the mechanistic links between PRMT1 dysregulation and disease pathogenesis. Further, the development and clinical potential of small-molecule inhibitors are also summarized. This review offers new perspectives on PRMT1-related disease mechanisms and lays a theoretical foundation for the development of targeted therapies. Ultimately, this review aims to contribute to the progression of precision medicine and the enhancement of global health outcomes.

Emerging evidence suggests that minimal residual disease (MRD) monitoring in solid tumors has implications for prognosis, treatment response, and therapeutic intervention. However, detecting MRD requires highly sensitive and specific circulating tumor DNA (ctDNA) assays. Therefore, we developed an innovative MRD monitoring assay that offers superior performance and cost advantage. Our approach utilizes a comprehensive genomic profiling panel to characterize the patient-specific mutational landscape of tumor tissue and selects up to 20 top-ranked variants to design a personalized panel, which is integrated with a tumor-naive cancer-type-specific fixed panel for ultra-deep sequencing of plasma ctDNA to monitor MRD in common solid tumors. Its limit of detection at the sample level reaches as low as 0.005%, with a specificity of 100%. Furthermore, when applied to colorectal, breast, and lung cancer patients, the ctDNA-MRD assay accurately predicted postoperative recurrence, prior to radiographic imaging by a median of 112 days for breast cancer and 83 days for lung cancer. In the tracked variants, clonal mutations demonstrated superior prognostic value compared to subclonal variants. This personalized MRD monitoring assay has the potential to enhance early detection of residual or recurrent disease, enable patient prognostic stratification, and inform clinical decision-making for patients with common solid tumors.

Posttraumatic osteoarthritis (PTOA) is a special form of osteoarthritis (OA), developing after joint injuries. Except for some minor clinical differences, no biologic marker has yet been identified to distinguish idiopathic OA (IOA) from PTOA. In this study, we investigated the expression of the stress-responsive cytokine growth differentiation factor 15 (GDF-15) in clinical samples from the Ulm OA study cohort and in a human ex vivo cartilage trauma model. GDF-15 levels were significantly higher in synovial fluid of PTOA patients as compared to IOA patients. We confirmed that fibroblast-like synoviocytes secreted GDF-15 after stimulation with medium of ex vivo-traumatized cartilage. Moreover, GDF-15 and its receptor, GFRAL, were elevated in highly degenerated OA cartilage. By means of a human cartilage trauma model, we discovered that chondrocytes produced GDF-15 upon tissue injury, while antioxidative treatment attenuated GDF-15 secretion. In fact, GDF-15 expression was mediated by oxidative stress and subsequent activation of p53. As a transcriptional target of p53, GDF-15 was associated with chondrosenescence. However, GDF-15 induced pro-regenerative response in chondrocytes, characterized by enhanced proliferation as well as chondro- and cell protection after cartilage trauma. Overall, this study first describes GDF-15 as a senescence-associated but potentially pro-regenerative cytokine in the context of human PTOA.

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by heterogeneous mutations in the tumor suppressor gene NF1. Neurofibromin, encoded by NF1, predominantly acts as a negative regulator of the RAS-MEK signaling pathway. Up to 30% of NF1 patients harbor nonsense mutations (NS) that introduce premature termination codons (PTCs). Ataluren is a well-characterized small molecule that acts as a nonsense suppressor by enhancing the ribosomal readthrough of PTCs. Here, we isolated primary fibroblasts from 22 Korean NF1^NS/+ patients and comprehensively evaluated the efficacy of ataluren treatment. The results demonstrate that hyperactivated GTP-bound RAS was significantly alleviated in approximately 23% of NF1^NS/+ fibroblasts, and the cellular levels of phosphorylated ERK also decreased in approximately 24% after ataluren treatment. Through transcriptome-wide profiling based on ataluren responsiveness, we analyzed a subset of genes in ataluren-treated NF1^NS/+ fibroblasts whose expression was significantly altered in ataluren-responsive cells, but not in nonresponsive cells. Furthermore, both AMPD3 and TGFBR3 were notably identified as feasible biomarkers for monitoring functional neurofibromin. Interestingly, AMPD3 can be an effective therapeutic target for NF1-associated diseases. Together, our study suggests that ataluren can be considered a therapeutic agent for some NF1^NS/+ patients and contributes to expanding insights into NF1 therapy.

The clinical outcome of Mycobacterium tuberculosis (Mtb) infection ranges from latent/nonprogressive disease to active/progressive tuberculosis (TB), but the cellular events contributing to these variable outcomes remain unknown. Here, we report that progressive Mtb infection is associated with upregulation of guanylate-binding protein-1 (GBP1), hypoxia-inducible factor-1 alpha (HIF-1α), and elevated NLR family pyrin domain-containing (NLRP3) inflammasome activation pathways. Using rabbit lungs and primary rabbit and human macrophages, as well as human monocytic THP-1-derived macrophages for infection with Mtb strains (H₃₇Rv, HN878, or CDC1551) that differ in virulence, we show that NLRP3 inflammasome activation by HIF-1α and GBP1 leads to elevated mitochondrial stress, apoptosis, and necrosis during progressive infection by HN878. These biological functions and pathways are dampened during nonprogressive TB in rabbit lungs, and in primary rabbit and human macrophages infected by CDC1551. These findings are consistent with and confirmed by Mtb infection studies of macrophages knocked down for HIF-1α or GBP1 expression. Our study indicates that differences in HIF-1α- and GBP1-mediated NLRP3 inflammasome activation influence the outcome of Mtb infection in the host.

This study aimed to assess the status of oral anticoagulant (OAC) therapy among Chinese patients with atrial fibrillation (AF) across various hospital departments, influenced by recent changes in medical insurance policies. It retrospectively analyzed data from 70,187 AF patients treated between January 2018 and December 2023 across 20 hospitals. The average patient age was 72.3 years, with 54.4% male. The study found a significant increase in OAC use over time, particularly in cardiology, where the usage rose from 29.8% pre-2018 to 68.8% in 2021–2023. However, OAC usage in non-cardiology departments remained below 50% during the same period. Tertiary hospitals had higher OAC prescription rates compared to non-tertiary hospitals. Despite 77.4% of the cohort being at high risk for stroke, their OAC usage rates were not higher than the non-high-risk group. Factors such as advanced age, history of bleeding, hemoglobin levels, and concurrent antiplatelet therapy hindered OAC use, while upstream treatments facilitated its acceptance. The study concludes that while progress has been made in OAC prescription in China, significant gaps remain, especially in internal medicine and surgery departments, necessitating targeted interventions and better interdisciplinary collaboration for improved patient outcomes.

The clinical performance of targeted therapies for treating hepatocellular carcinoma (HCC) is significantly limited by the frequent emergence of drug resistance, ultimately resulting in therapeutic failure and poor prognosis. While the precise mechanisms underlying this resistance are not fully elucidated. Emerging evidence implicated that reactive oxygen species (ROS) homeostasis and ferroptosis, a unique form of programmed cell death, are closely associated with the development of drug resistance in cancer cells. In this study, we demonstrated that circRNA-SORE, a circRNA previously reported by our group, played a crucial role in mediating sorafenib resistance via regulating intracellular ROS levels and inhibiting ferroptosis. Mechanically, we identified that circRNA-SORE exerted its regulatory effects through modulating the level of UBQLN1. UBQLN1, via its STI domain, stabilized GPX4, a crucial antioxidant enzyme that protects against ferroptosis death. The stabilization of GPX4 promoted cancer cell survival under sorafenib-induced oxidative stress. In conclusion, this study revealed a novel circRNA-SORE/UBQLN1/GPX4 regulatory axis that mediated sorafenib resistance in HCC and also offered a promising therapeutic strategy to overcome drug resistance and improve clinical outcomes for patients with HCC.

Endovascular surgical robots have advanced vascular surgery through the integration of automatic programs for complex interventions. However, current systems still lack full procedural automation capabilities. This single-center single-arm study explores the feasibility and safety of automatic robotic-assisted endovascular aortic repair (EVAR) using a novel surgical algorithm with in vitro and in vivo experiments. The EVAR process was deconstructed into surgical steps and programmed into an endovascular surgical robot, which executed the steps automatically based on parameters derived from image processing software. In vitro experiments using 3D-printed vascular models demonstrated millimeter-level precision, with reduced operation time, fluoroscopy time, and radiation exposure compared to manual robotic control. In vivo evaluations in four patients with abdominal aortic aneurysms achieved 100% technical and clinical success, with no major adverse events. Operation time averaged 110 ± 47 min, fluoroscopy time was 19 ± 6 min, and patient-side radiation exposure was 1251 ± 389 mGy. Surgeon-side radiation exposure was 4 ± 1 mGy. The results indicate that automatic robotic-assisted EVAR can be performed with acceptable accuracy and safety to provide standardized therapies, shorten operation time, and reduce radiation exposure of patients.

Colorectal cancer (CRC) is a complex and heterogeneous disease with limited effective treatment options. To investigate the molecular features and potential therapeutic strategies for CRC patients, including both early-onset colorectal cancer (EOCRC) and late-onset colorectal cancer (LOCRC) cases, a comprehensive multi-omics approach was employed. Whole exome sequencing (WES), RNA sequencing (RNA-seq), and proteomic and phosphoproteomic profiling were performed on paired tumor and normal adjacent tissue (NAT) from 144 CRC patients, totaling 672 samples. Three distinct molecular subtypes were identified, each exhibiting unique clinical prognoses and molecular characteristics. The S_I subtype was associated with the worst prognosis and a greater prevalence of EOCRC. Moreover, it exhibited a higher stromal score, characterized by increased infiltration of fibroblasts, mesenchymal stem cells, and adipocytes, when compared with the S_II and S_III subtypes. Additionally, the S_II subtype showed a higher immune score. Drug testing using cell lines and patient-derived three-dimensional (3D) bioprinted models revealed that S_I tumors were more responsive to Alisertib, suggesting subtype-specific therapeutic potential. Our study characterized the multi-omics landscape of CRC, offering critical insights into its molecular heterogeneity. These findings enhance our understanding of the molecular mechanisms underlying CRC and contribute to the development of personalized treatment strategies.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor prognosis. Cluster of differentiation 36 (CD36), a fatty acid transporter, plays controversial roles in tumor progression. Here, we report a tumor-suppressive function of CD36 in TNBC. Analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases, along with validation in clinical samples, revealed that CD36 expression was significantly downregulated in TNBC tissues, and its low expression correlated with advanced disease stage and poorer patient prognosis. Functional assays demonstrated that CD36 knockout promoted, whereas its overexpression inhibited, the proliferation, migration, and invasion of TNBC cells. Integrated transcriptomic and proteomic analyses linked CD36 to ferroptosis, an iron-dependent form of regulated cell death. Mechanistically, CD36 enhanced the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ), which in turn upregulated the expression of caveolin-1 (CAV1). This CD36/PPARγ/CAV1 axis increased intracellular lipid peroxidation, thereby promoting ferroptosis. In vivo, a CD36 agonist suppressed, while a ferroptosis activator inhibited the metastasis of CD36-knockdown TNBC cells. Our findings identify CD36 as a novel tumor suppressor in TNBC that acts by promoting ferroptosis, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Obesity is a recognized risk factor for cancer development and progression. Paradoxically, growing clinical evidence across several cancer types indicates that elevated body mass index (BMI) or specific body composition characteristics—such as increased visceral fat or preserved skeletal muscle—may be associated with moderately improved overall survival in patients undergoing immune checkpoint inhibitor (ICI) therapy. This seemingly contradictory phenomenon is often described as the “obesity paradox.” In this review, we delineate the etiological versus therapeutic implications of obesity, synthesizing data from non-small cell lung cancer, renal cell carcinoma, melanoma, and hepatocellular carcinoma. Proposed explanations include low-grade inflammation with signal transducer and activator of transcription 3-mediated programmed death-1 upregulation, insulin/insulin-like growth factor-1 signaling, adipokine imbalance, stromal fibrosis and hypoxia, and metabolic reprogramming that may alter T-cell function and tumor immunogenicity. Nonbiological factors—including dosing strategies, sarcopenia, and sex-specific differences—are also examined. We advocate for future research employing comprehensive body composition assessments, standardized pharmacokinetic/pharmacodynamic analyses, and consideration of sex and metabolic health. Clarifying the temporal and mechanistic basis of the obesity–ICI benefit relationship will inform the optimization of cancer immunotherapy.

Peroxiredoxin 1 (PRDX1) overexpression in colorectal cancer (CRC) correlates with poor prognosis and reduced T-cell infiltration. However, the mechanism underlying PRDX1-mediated immune suppression remains elusive. In this study, we found that knockout of PRDX1 robustly suppressed AOM/DSS-induced colonic adenocarcinoma compared with wild-type C57BL/6J mice, accompanied by highly infiltrated CD4⁺/CD8⁺ T cells and reduced CD163⁺ tumor-associated macrophages (TAMs). Furthermore, PRDX1 knockdown in CRC cells inhibited M2 macrophage polarization by impairing hypoxia-inducible factor 1α (HIF-1α)/GLUT-1-mediated glycolysis and lactate secretion. Mechanistically, PRDX1 binds to Cullin-2 as a molecular chaperone, thereby suppressing ubiquitination and degradation of HIF-1α. The PRDX1^Cys83Ser mutant abolished the ability to bind to Cullin-2, suggesting that Cys83 is an active site of PRDX1 in regulating HIF-1α/GLUT-1-mediated glycolysis. Importantly, PRDX1 deletion in macrophages reversed the immunosuppressive phenotype and reciprocally enhanced the phagocytosis, inhibited CRC cell growth and migration. Cytokine assay demonstrated that PRDX1 deficiency increased IL-1β and TNF-α secretion by activating the JAK/STAT1/NF-κB pathway, promoting M1 macrophage polarization. Notably, PRDX1 knockout macrophages inhibited syngeneic tumor growth and enhanced sensitivity to anti-PD-1 therapy in vivo. In conclusion, targeted deletion of PRDX1 enhances anti-tumor immunity in CRC by reprogramming the immunosuppressive TAMs, revealing a novel role of PRDX1 as a potential drug target during anti-tumor immunotherapy.

Cancer is more than just a collection of tumor cells. The complex tumor system, including the tumor immune microenvironment (TIME), is continually changing. Tumor cells are in constant communication with all stromal elements (e.g., fibroblasts, endothelial cells, and extracellular matrix) and immune effector cells (e.g., T cells, B cells, natural killer cells, dendritic cells, macrophages, and myeloid-derived suppressor cells). Together, these intricate interactions among cell and molecular signaling pathways collectively drive tumor growth, tumor invasion, and metastasis and significantly affect the efficacy of cancer treatments. Recent investigations, from a tumor-centric research paradigm to a complete evaluation of the local tumor microenvironment, have revealed the importance of the TIME. Although reviews in these fields typically focus on cellular/molecular breakdowns of the TIME and evasion of the immune system, a systematic study of its dynamic evolution is lacking. This review comprehensively discusses the major regulators and networks involved in the dynamic evolution of the TIME, the spatiotemporal dynamics of TIME components, metabolic reprogramming as an engine of TIME evolution, the targeting of metabolic regulators, and niches for TIME modulation, clinical and translational challenges, and future prospects. This information could help researchers explore the TIME and generate new therapeutic strategies.

Surgical intervention is vital for treating neural system tumors, with precise intraoperative determination of tumor boundaries crucial for safe and effective surgery. Optical coherence tomography (OCT), offering noninvasive, real-time imaging, presents a promising solution. This study developed a swept-source OCT system using a 1310 nm wavelength laser, enhanced by microelectromechanical systems technology for improved scanning accuracy. Neural tumor specimens and peritumoral tissues were analyzed, alongside evaluations in animal models, including rats and mice with gliomas, schwannomas, and meningiomas, to assess the system's real-time surgical application. Results revealed significantly lower light attenuation in human glioma samples than in peritumoral tissues (p = 0.019), with an receiver operating characteristic curve area under the curve of 0.846. Gliomas exhibited higher pixel values and gentler trend line slopes (p < 0.001). Animal models showed the OCT system was capable of detecting nerves and their epineurium located deep to schwannomas and meningiomas (at depths <3 mm), which appeared as thin, tubular, or crescent-shaped images with higher density compared with the surrounding tissue. These findings highlight the OCT system's ability to differentiate tumor from nontumoral tissues, demonstrating its potential as a handheld tool for precise boundary detection in neurosurgery. This advancement represents a promising step toward improving the accuracy of tumor resection.

USP30, a ubiquitin-specific protease, primarily characterized as a mitochondrial deubiquitinase regulating mitophagy, has not been previously reported to have nuclear functions. In this study, we demonstrate that USP30 is present in both mitochondrial and nuclear compartments. Nutrient deprivation triggers USP30 nuclear translocation via an N-terminal nuclear localization signal (NLS), mediated through suppression of mTORC1-dependent phosphorylation at serine 104, a modification constraining nuclear entry. Nuclear USP30 acts as a tumor suppressor by inhibiting cancer stemness and chemoresistance in triple-negative breast cancer (TNBC) cells. Mechanistically, USP30 directly interacts with and deubiquitinates the transcription factor TCF/LEF1 at K379 and K382 residues, disrupting recruitment of CBP/P300 co-activators to the β-catenin/LEF1 complex. This abolishes β-catenin/LEF1 transactivation and suppresses WNT signaling. Clinically, USP30 is downregulated in TNBC and cancer stem cells (CSCs), with notably reduced nuclear levels in cancer tissues. Overexpression of nuclear USP30 markedly reduces lung metastatic burden in TNBC mouse models. These findings uncover a novel role for nuclear USP30 in regulating cancer stemness and suggest that targeting the dynamic relocalization of USP30 from mitochondria to the nucleus could offer new therapeutic strategies for breast cancer metastasis.

The histone deacetylases (HDACs) family plays a critical role in tumorigenesis and has been identified as having a significant impact on tumor immunity. Herein, we employed a fragment-centric structure-based design platform, leading to the discovery of SDFZ-8 as a highly potent HDAC1 inhibitor (IC₅₀ = 0.4 nM). SDFZ-8 exhibits strong antiproliferative effects by enabling histone acetylation and inducing cell apoptosis. Crucially, SDFZ-8 treatment led to a significant enhancement of antitumor immunity, as evidenced by increased activation of T cells, enhanced polarization of M1-type macrophages, improved antigen presentation, and alleviation of the immunosuppressive tumor microenvironment. Specifically, we observed that SDFZ-8 notably upregulated the expression of PD-L1 in both tumor cells and tumor-infiltrating lymphocytes, which is closely associated with its inhibition against HDAC1. Of particular interest, combining SDFZ-8 with PD-L1 blockade resulted in a synergistic antitumor effect surpassing that of either monotherapy. Taken together, our findings establish SDFZ-8 as a novel HDAC1 inhibitor that concurrently targets tumor cells and immune evasion mechanisms, providing a rational combinatorial strategy to enhance cancer immunotherapy efficacy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease globally. Previous studies have shown that MASLD is an independent risk factor for chronic kidney disease (CKD), but the variations in estimated glomerular filtration rate (eGFR) levels across countries with different ethnic backgrounds have not been extensively reported. We enrolled 3308 participants with biopsy-proven MASLD from 34 centers in this multinational study and analyzed the associations between eGFR and histological severity of liver fibrosis in different countries. European participants had lower eGFR levels (92.2 ± 20.7 vs. 104.7 ± 17.3 mL/min/1.73 m²) and significant liver fibrosis (61.4 vs. 32.4%) than Asian individuals. In Asia, Chinese participants had the highest mean eGFR level at 105.8 mL/min/1.73 m², while Malaysian participants had the lowest at 87.3 mL/min/1.73 m² (p < 0.001). In Europe, French participants had the highest mean eGFR level at 95.3 mL/min/1.73 m², while Romanian individuals had the lowest at 81.1 mL/min/1.73 m² (p < 0.001). eGFR levels were inversely associated with liver fibrosis in Asian individuals (OR: 0.793, 95%CI: 0.685–0.917, p = 0.002), even after adjusting for traditional renal risk factors, but not in Europeans. Our findings provide the basis for further investigation of the burden of MASLD on CKD risk in different countries.

Immune checkpoint inhibitors (ICIs) are widely used for treating hepatocellular carcinoma (HCC), yet their efficacy remains limited, with suboptimal response rates. The predictive power of the current biomarker, programmed death ligand-1 (PD-L1), is limited by detection variability and glycosylation, underscoring the need for complementary biomarkers to enhance predictive accuracy. In this study, mass spectrometry was employed to identify proteomic alterations in HCC tissues from responders and nonresponders to anti-programmed cell death-1 (PD-1) therapy. Survival analysis established the role of Yin Yang 1 (YY1) in determining ICI efficacy. Coculture models of hepatoma and CD8⁺ T cells revealed the immunosuppressive function of YY1. Transcriptome sequencing identified polypeptide N-acetylgalactosaminyltransferase 16 (GALNT16) as a transcriptional target of YY1, and subsequent Western blot and coimmunoprecipitation assays demonstrated that GALNT16 augments PD-L1 expression. Furthermore, in vivo mouse models demonstrated that YY1 knockdown potentiated the efficacy of anti-PD-1 therapy, an effect that was partially reversed by GALNT16 overexpression. Specifically, YY1 upregulates GALNT16, which in turn promotes PD-L1 glycosylation and stability, leading to diminished CD8⁺ T cell activity. Thus, GALNT16 knockdown rescued the compromised CD8⁺ T cell cytotoxicity induced by YY1. Collectively, these results elucidate the YY1/GALNT16/PD-L1 axis as a pivotal mechanism underlying HCC resistance to ICI therapy. This highlights the therapeutic potential of targeting PD-L1 glycosylation pathways.

This study aimed to investigate the effect of lipoprotein(a) (Lp(a)) on major adverse cardiovascular events (MACEs) among individuals with chronic coronary syndrome (CCS) according to ABO blood groups. Two independent cohorts of patients with CCS were included consecutively. Blood groups and Lp(a) levels were measured. Patients with the AB group were excluded due to the small sample size. In the exploratory cohort (n = 7611), 560 MACEs were recorded over a mean follow-up of 54.80 months. Stratification analysis revealed that the relationship of elevated Lp(a) levels with prognosis was more pronounced in patients with blood group A or B. Patients with blood group A or B plus medium Lp(a) (HR, 1.93, 95% CI: 1.24–3.01) or high Lp(a) (HR, 2.06, 95% CI: 1.32–3.24) concentrations had a significantly higher risk of MACEs compared to those with blood group O and low Lp(a) levels. Similar results were obtained in the confirmatory cohort (n = 7916). In conclusion, our data demonstrated for the first time a more prominent association between Lp(a) and adverse outcomes in CCS patients with non-O blood group compared to those with blood group O, suggesting that ABO blood group measurement may be clinically useful for decision-making in Lp(a) intervention.

Metabolic syndrome (MetS) poses a significant risk to the cerebrovascular system, impacting the prognosis of stroke patients. This study investigated the link between MetS and stroke-related outcomes, exploring tissue kallikrein 1 (KLK1) as a potential mediator. In the derivation cohort, a total of 17,106 stroke-diagnosed patients were assessed, with 6917 individuals (40.4%) presenting comorbid MetS. Multifactorial analysis identified stroke concurrent with MetS (adjusted odds ratio = 1.42; 95% confidence interval: 1.17–1.72; p < 0.001) as a risk factor for unfavorable outcomes among stroke patients. Further bioinformatics analyses indicated that obesity, diabetes, and hypertension were associated with reduced KLK1 levels (all p < 0.05). In the validation cohort, 1268 first-ever stroke patients were enrolled, confirming a higher incidence of adverse outcomes in those with MetS, compared with those without (223 (28.1%) vs. 167 (35.2%); p < 0.01). Stroke patients with MetS, exhibited lower KLK1 levels (16.8 ± 6.52 vs. 15.6 ± 6.3; p < 0.01). Mediation analyses supported that MetS contributed to adverse outcomes through the mediating effect of decreased KLK1 levels (p < 0.05). This study highlights the risk of MetS in stroke patients and suggests a potential role for KLK1 as a mediating factor.

Clinical trial registration: Not applicable.

Everolimus (EVE) combined with letrozole is an approved treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC). However, predictive biomarkers for EVE efficacy remain undefined. In the phase 2 MIRACLE trial, we performed digital spatial profiling (DSP) on pretreatment tumor samples from 21 patients receiving EVE plus letrozole. Patients were divided into resistant and sensitive groups based on their best response to EVE. A total of 119 regions across three compartments—tumor, leukocytes, and stroma—were profiled for immune and transcriptomic markers. Responders had significantly higher fibroblast infiltration in PANCK+ (p = 0.011) and CD45−/PANCK− (p = 0.043) regions, whereas non-responders exhibited increased neutrophils in CD45+ (p = 0.0061) and PANCK+ (p = 0.03) regions. Prolactin-induced protein (PIP) mRNA expression was significantly elevated in non-responders in both PANCK+ (p < 0.0001) and CD45−/PANCK− (p = 0.0006) regions. PIP mRNA expression was found to be associated with EVE resistance and unfavorable progression-free survival (PFS). PIP mRNA expression and specific immune-stromal features are associated with resistance to EVE. These findings suggest the potential of PIP as a spatially resolved predictive biomarker for patient stratification in HR+/HER2− ABC.

This study evaluated the safety, tolerability, and pharmacokinetics of JBD0131, a novel nitroimidazooxazole antitubercular agent, in healthy adults. We previously reported JBD0131, a novel nitroimidazooxazole antitubercular agent, which overcomes drug resistance and bioavailability limitations of existing anti-tuberculosis therapies. The clinical trial was structured into three parts: an initial single ascending dose (SAD) phase under fasting conditions, a food-effect assessment, and a final multiple ascending dose (MAD) phase conducted after meals. Among 95 enrolled participants, JBD0131 demonstrated favorable safety and tolerability across all regimens. No serious adverse events (AEs) or treatment discontinuations occurred. Treatment-emergent AE incidence was comparable to placebo without dose-dependent trends. Pharmacokinetic (PK) analysis showed that systemic exposure for JBD0131, measured by maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC), increased proportionally with the dose. The presence of food significantly enhanced the bioavailability and delayed the median time to reach peak concentration (T_max) by approximately 2 h. These findings collectively demonstrate that JBD0131 has an acceptable safety profile and predictable, linear pharmacokinetics in healthy adults. The observed food effect, which boosts systemic exposure, along with the drug's linear accumulation, supports the need for further investigation to define optimal treatment regimens for future clinical development.

Gastrointestinal cancers, including gastric, hepatic, and colorectal cancers, represent a major public health problem globally. Although the 5-year survival rate of gastrointestinal tumors has been greatly improved due to the progress of diagnostic and therapeutic strategies, therapeutic resistance and distant metastasis remain the leading causes of cancer-related death in patients with gastrointestinal tumors. Cancer stem cells (CSCs) are a population of self-renewal cells with extremely strong carcinogenic potency, contributing to the progression, metastasis, and therapeutic resistance of gastrointestinal tumors. It is generally accepted that gastrointestinal CSCs have the characteristics of self-renewal, pluripotency, tumorigenicity, metastatic potential, and therapeutic resistance. Hence, understanding the behaviors of gastrointestinal CSCs is important for characterizing the stemness landscapes of gastrointestinal tumors and developing promising strategies for the treatment of gastrointestinal tumors. This review aims to discuss the basic characteristics of gastrointestinal CSCs, existing approaches to define and isolate CSCs, and canonical molecular pathways involved in the regulation of gastrointestinal CSCs. More importantly, potential strategies targeting gastrointestinal CSCs are proposed to overcome the limitations of current therapies.

Dengue virus (DENV) is an acute infectious pathogen worldwide, for which no effective therapeutics are available. The RNA-dependent RNA polymerase (RdRp) displays an important role during DENV replication and is therefore a promising target in the development of antiviral drugs. However, there are still no clinically approved RdRp inhibitors available. In this study, we identified a natural small molecule, 12β-hydroxydammar-3-one-20(S)-O-β-d-glucopyranoside (PN-1), using a surface plasmon resonance-based screening assay. Biochemical and structural analyses revealed that PN-1 selectively targets the RdRp of DENV NS5 protein by covalently modifying residues Glu255, Met387, Glu479, and Ala507. Mechanistic studies involving tryptophan scanning and hydrogen-deuterium exchange mass spectrometry revealed that PN-1 binding regulates RdRp conformational transitions. This allosteric mechanism leads to suppression of enzymatic activity and inhibition of DENV replication. Consequently, PN-1 exhibited potent antiviral activity across various cell lines and conferred significant protection in both ICR suckling and AG129 mouse models. Taken together, our results show that PN-1 functions as a novel non-nucleoside inhibitor to suppress DENV replication by targeting RdRp. These findings highlight PN-1 as a promising anti-DENV lead compound, while revealing conserved RdRp residues as actionable targets for rational drug design.

Immunosenescence denotes progressive deterioration of immune system during physiological aging, initially recognized by the observation of heightened susceptibility to diverse pathologies in elder population. Beyond exhibiting canonical cellular senescence features, senescent immune cells manifest multidimensional dysfunction characterized by impaired secretory capacity and functional disorders. This process further triggers systemic epigenetic dysregulation and failure in damage repair, which collectively remodel metabolic and inflammatory microenvironments to attenuate immune responses and elevate risks of diverse degenerative diseases or multiple types of cancer. Critically, senescence-associated secretory phenotype (SASP) factors secreted by senescent cells display profound disease-associated content and spatial–temporal heterogeneity, engaging in bidirectional crosstalk with pathological progression through interconnected signaling axes. Reciprocally, both pathogenic evolution and therapeutic pressures are confirmed to exacerbate immunosenescence, driving impaired replenishment of immune cells and pathological accumulation of immunosuppressive factors that impact disease progression and poor outcomes. As indicated by clinical evidence, senotherapies designed to eliminate senescent cells or block SASP signaling have emerged as promising interventions to ameliorate age-related pathologies. In this review, we systematically combed and delineated disease-specific immunosenescent hallmarks, dissect disease–immunosenescence interplay patterns, and evaluated the translational value of immunosenescence-targeting strategies.

Multidrug resistance (MDR) remarkably hinders the success of clinical chemotherapy in carcinomas. The ATP-binding cassette (ABC) transporter as ABCB1, ABCG2, and ABCC1 are most crucial to drive MDR. Regrettably, no MDR modulators have been accepted in clinic. Herein, KSQ-4279, a first-in-class ubiquitin-specific peptidase 1 (USP1) inhibitor in clinical development, was found as a pan-MDR modulator. Our study showed that KSQ-4279 strikingly intensified the cytotoxicity of multiple classical chemotherapeutic drugs in ABCB1/ABCG2/ABCC1-induced MDR cancers independent of its own cytotoxicity in vitro, and remarkably improved chemotherapeutic efficacy not only in ABCB1/ABCG2/ABCC1-overexpressing tumor xenografts in vivo, but also in ABCB1-overexpressing clinical lung cancers ex vivo. Mechanistically, KSQ-4279 weakened ABCB1/ABCG2/ABCC1 efflux function, thus increasing drugs’ reservation in cells; more specifically, it was achieved by KSQ-4279 activating the ATPase activity and competing for the substrate-binding pockets of ABCB1/ABCG2/ABCC1. Besides, at the effective reversal concentrations, KSQ-4279 neither altered expression and localization of ABCB1/ABCG2/ABCC1, nor affected USP1's potential downstream AKT or ERK1/2 signaling. This is the first study to investigate the combination of USP1 inhibitor (KSQ-4279) with traditional chemotherapeutic drugs in reversing MDR, which surprisingly hinted ABCB1, ABCG2, and ABCC1 as the new targets of KSQ-4279, and advocated this promising combination therapy in clinical refractory MDR cancers.

Musculoskeletal diseases encompass a broad spectrum of inflammatory, degenerative, and neoplastic disorders that compromise bone and joint function across the lifespan. Increasing evidence highlights the central role of immune regulation in their pathogenesis, driven by complex interactions among immune, bone, and stromal cells. Inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and dermatomyositis are marked by persistent immune activation and progressive tissue destruction. Degenerative diseases like osteoarthritis, osteoporosis, and intervertebral disc degeneration involve immune senescence, dysregulated tissue remodeling, and inflammation-driven structural damage. Bone and soft tissue tumors—including osteosarcoma, chondrosarcoma, Ewing sarcoma, and soft tissue sarcoma—develop within immunosuppressive niches that hinder antitumor immunity. Notably, these immune environments are not strictly dichotomous but exhibit dynamic, context-dependent states of immune stimulation and suppression. This review delineates both shared and disease-specific immune mechanisms, spanning cytokine networks, signaling pathways, and cellular interactions. It further discusses current and emerging therapeutic strategies, including cytokine modulators, bone-regulatory agents, immune checkpoint inhibitors, and cell-based therapies. Despite recent advances, key challenges persist in translating immunological insights into durable, disease-modifying treatments. By bridging mechanisms across inflammation, degeneration, and malignancy, this review provides an integrated framework for understanding immune contributions to musculoskeletal diseases and identifies promising directions for precision immunotherapy.

Lysine acetyltransferase 6 (KAT6) consists of KAT6A and its paralog KAT6B, which represent crucial regulators for epigenetic modifications. By acylating histone H3 and nonhistone proteins, KAT6 enzymes play predominant roles in transcription, cell cycle, diverse developmental processes, regulation of the immune system, and self-renewal and maintenance of hematopoietic and neural stem cells. Importantly, the frequent molecular dysregulation of KAT6A and KAT6B correlates with survival outcomes of cancers, contributing to the exploration of a wide array of small-molecule inhibitors against KAT6 catalytic activity. Recent progress in drug discovery has led to the development of dual KAT6A and KAT6B inhibitors with potent antitumor efficacy and selectivity in both preclinical and clinical settings, supporting KAT6 as a druggable, promising target for the treatment of cancers, particularly breast cancers. In this review, we summarize the currently available information regarding the physiological and pathological functions of KAT6A and KAT6B and discuss their potential as antitumor targets in drug development. We also present the discovery and development of an emerging class of KAT6 inhibitors under investigation for breast cancer, along with potential molecular mechanisms underlying the therapeutic efficacy of targeting KAT6, providing references for developing therapeutic strategies in clinical practice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and irreversible alveolar destruction. Despite advances in antifibrotic therapies, the underlying pathogenic mechanisms remain incompletely understood. Recent multiomic studies have revealed that IPF arises from aberrant communication among epithelial, mesenchymal, immune, and vascular cells within the fibrotic microenvironment, rather than from isolated cellular dysfunction. However, the dynamic intercellular networks and spatiotemporal regulation driving disease progression remain poorly defined. This review integrates recent single-cell RNA sequencing and spatial transcriptomic discoveries to delineate key pathogenic cell populations—including aberrant basaloids and IPF-related alveolar type 2 cells (IR_AT2), CTHRC1⁺ and meflin⁺ fibroblasts, and SPP1^hi macrophages—and their signaling crosstalk through pathways such as transforming growth factor β(TGF-β), Hippo, and Hedgehog. We further discuss how ECM feedback loops and immune-metabolic remodeling reinforce fibrogenesis and explore emerging therapeutic targets derived from these mechanisms. By synthesizing multidimensional data into a cellular and molecular framework, this review advances the understanding of IPF pathogenesis and provides a conceptual foundation for biomarker-guided precision therapies.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that promotes cancer cell proliferation, invasion, and drug resistance. In this study, CIP2A expression was found to be higher in lung cancer tissues compared to adjacent normal tissues. Knocking down CIP2A in lung cancer cells reduced cell proliferation and migration. Ring finger protein 1 (RING1), a member of the RING family in the ubiquitin–proteasome system, was identified as a potential E3 ligase for CIP2A. The interaction between RING1 and CIP2A was confirmed, with RING1 regulating CIP2A ubiquitination. Knockdown of RING1 increased lung cancer cell proliferation and migration in vitro and in vivo, linked to the upregulation of CIP2A and its downstream molecules, c-MYC and Cyclin B1. Smoking's impact on RING1 expression was examined using cigarette smoke extract (CSE), which decreased RING1 mRNA and protein levels. This led to CIP2A and c-MYC upregulation. The carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a constituent of CSE, downregulated RING1 expression through DNA methyltransferase 1 (DNMT1) activation, whereas inhibition of DNMT1 restored RING1 levels. These findings highlight the DNMT1–RING1–CIP2A axis in lung cancer progression due to smoking and suggest potential therapeutic and diagnostic targets.

Cell mechanics is a fundamental regulator of numerous cellular processes, orchestrating critical biological activities spanning from embryogenesis to senescence. Cells continuously sense and respond to mechanical cues through specialized interactions between membrane-bound adhesion proteins, such as integrins, and adhesive ligands within the extracellular matrix (ECM). This bidirectional interaction forms the basis of mechanotransduction—a complex, dynamic process that ultimately leads to alterations in nuclear mechanics and governs essential cellular functions, including migration, tissue morphogenesis, and so on. In this review, we provide an overview of these dynamic cell–ECM interactions and delve into the intricate molecular mechanisms underlying mechanotransduction. We further introduce advanced research methodologies and emerging clinical tools used to investigate cellular mechanical phenotype, mechanotransduction, and diseases progression. In addition, we analyzed the roles of mechanical biomarkers in the development and progression of cancer, fibrosis, and aging. We highlighted the necessity of drug development targeting mechanotransduction, providing examples of drugs that have already entered clinical trials and preclinical tools. By integrating current findings and outlining emerging perspectives, this review aims to provide critical insights and inspire future efforts in understanding, manipulating, and clinically exploiting mechanotransduction-targeted markers to regulate the progression of diseases such as cancer, fibrosis, and aging.

Evidence for the use of prophylactic anti-seizure medication (ASM) in traumatic brain injury (TBI) in reducing the occurrence of early post-traumatic seizure (EPTS) remains equivocal. This study aimed to analyze the prevalence of EPTS in children with TBI, compare clinical characteristics of those with and without EPTS, and explore the association between prophylactic ASM and EPTS. We performed an observational study among 28 pediatric intensive care units in 15 countries from January 2014 to October 2022. The rate of EPTS was compared between individuals prescribed prophylactic ASM and those who were not. Logistic regression was used to examine the association between ASM and EPTS. Among 697 children with TBI, 161 (23.1%) developed EPTS and 280 (40.2%) received prophylactic ASM treatment. Use of prophylactic ASM was associated with a lower likelihood of developing EPTS (27/280 (9.6%) vs. 134/417 (32.1%), p < 0.001). The most frequently used prophylactic ASMs were phenytoin, levetiracetam, and phenobarbital. Age ≤ 4 years and GCS ≤ 8 were associated with increased odds of developing EPTS (aOR 2.29, 95% CI 1.54–3.40, p < 0.001 and aOR 1.80, 95% CI 1.18–2.74, p = 0.01). Our data provide evidence supporting the potential protective role of prophylactic ASM against EPTS.

E3 ubiquitin ligases are pivotal regulators within the ubiquitin–proteasome system, conferring specificity to protein ubiquitination and subsequent degradation, thereby maintaining cellular homeostasis. Their structural diversity allows for the precise control of vital processes, including the cell cycle, immune responses, and signal transduction, across various tissues. Despite their profound influence on physiology, a systematic understanding of how specific E3 ligases contribute to distinct disease pathogenesis and their translational potential remains incomplete. This review systematically delineates the classification and catalytic mechanisms of major E3 ligase families, including RING, HECT, and RBR types, and elaborates their pathological roles in driving carcinogenesis, cardiovascular remodeling, autoimmune dysregulation, metabolic syndrome, and neurodegenerative aggregation. We further synthesize recent advances in therapeutic modalities, from small-molecule inhibitors targeting ligases like MDM2 to novel strategies in targeted protein degradation, notably proteolysis-targeting chimeras (PROTACs) that hijack E3 machinery. By integrating mechanistic insights with emerging therapeutic landscapes, this work underscores the central role of E3 ligases in human diseases and provides a strategic framework for developing next-generation, mechanism-based therapeutics.

The diagnosis and management of disorders of consciousness (DoC) remain a critical challenge in clinical medicine and neuroscience. The key bottleneck is the lack of reliable biomarkers and an incomplete understanding of the pathophysiological mechanisms that underlie DoC. In view of this, a bedside-compatible, multimodal technique based on electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) was utilized to simultaneously capture neuronal oscillations and accompanying hemodynamics, so as to explore neurovascular biomarkers that can effectively discriminate different states of DoC. Resting-state EEG-fNIRS data from 13 regions of interest (ROIs) were acquired and compared across healthy controls (HC), minimally conscious state (MCS), and unresponsive wakefulness syndrome (UWS) groups. Hemodynamics-based functional connectivity and the spectral power of neuronal activity were quantified and subsequently employed to interrogate neurovascular coupling. The results demonstrated significantly stronger neurovascular coupling and beta-band power in premotor and Broca's areas of the MCS group. A multimodal classifier achieved an accuracy of 87.9% in distinguishing between MCS and UWS. The noninvasive, bedside-suitable nature of this tool underscores its potential for routine monitoring and prognostic assessment in DoC, addressing a critical need for accessible and reliable biomarkers in both neurology and intensive-care practice.

Organoids are three-dimensional structures that closely resemble the architecture and functions of human organs, offering key advantages over traditional models by better replicating tissue complexity and cellular interactions. These systems have become invaluable tools for disease modeling, drug screening, and regenerative medicine applications. Despite this progress, their lack of immune components limits their usefulness in diseases where immune cells are central drivers of pathology and therapy. The absence of an immune system within organoids limits their physiological relevance, particularly for cancer, inflammation, and autoimmunity research. Immune cell-containing organoids provide a comprehensive platform for immunotherapy, host–pathogen interactions, regeneration, and immune disorders. This review first highlights the transformative potential of immune cell-containing organoids across cancer, infection, inflammation, autoimmunity, regeneration, and the modeling of primary lymphoid organs. It then examines current strategies for integrating immune cells into organoids, the variety of immune cell sources employed, and the challenges in maintaining immune cell function. Finally, the role of bioengineering, biobanking, and artificial intelligence in overcoming existing limitations and enhancing immune system modeling is discussed. Overall, this study positions immune cell-containing organoids as powerful platforms for translational research and precision medicine.

Alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are among the most prevalent chronic liver conditions globally, placing a substantial burden on global healthcare systems. Although significant progress has been made in their study, the pathogenic mechanisms remain incompletely defined, and effective treatments are still limited. This review aims to provide a comprehensive analysis of the shared and divergent molecular pathogenic mechanisms underlying these two diseases and to systematically summarize the latest therapeutic intervention strategies. Although ALD and MASLD have distinct etiologies, they share multiple pathophysiological pathways, such as dysregulated lipid metabolism, programmed cell death, cellular senescence, gut dysbiosis, and immune activation. We focus on key molecular events within these shared pathways, such as impaired fatty acid oxidation, increased lipogenesis, activation of pyroptotic and necroptotic signaling pathways, engagement of the p53–p21 senescence axis, and gut microbiota-driven immune signaling pathways via microbial metabolites and microbe-associated molecular patterns. Building upon these mechanistic insights, the review further outlines therapeutic strategies targeting lipid metabolism, cell death, cellular senescence, microbiota modulation, and immunomodulation, while also discussing the specific challenges and opportunities. Ultimately, this review proposes a mechanistic framework to guide the development of precision therapies for ALD and MASLD.

O-GlcNAcylation is a reversible posttranslational modification of proteins that has garnered significant attention in recent years. By regulating the structure and function of proteins, it plays a critical role in various biological processes. Normal O-GlcNAcylation is essential for maintaining internal homeostasis and is involved in controlling fundamental biological events such as gene expression, the cell cycle regulation, metabolism, and signal transduction. Conversely, aberrant O-GlcNAcylation is closely linked to the onset and progression of various diseases—including neurodegenerative diseases, cancers, cardiovascular diseases, and immune-related diseases—where it drives pathological development. Currently, there is a lack of comprehensive reviews systematically addressing the specific mechanisms of O-GlcNAcylation under both physiological and pathological conditions. Therefore, this article aims to summarize its dual role in maintaining organismal homeostasis and promoting disease pathogenesis, providing an integrated evaluation of the biological significance of this modification in health and diseases. Furthermore, it discusses the potential of O-GlcNAcylation as a therapeutic target, explores its clinical applications, and analyzes the current challenges and future directions in drug development, thereby offering theoretical insights and research perspectives for related fields.

Trial registration: Chictr.org.cn, ChiCTR2200065547. Registered in 2022-11-08, https://www.chictr.org.cn/showproj.html?proj=183439.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a growing global burden. Current pharmacological therapies remain limited to symptomatic management, owning to an incomplete understanding of the mechanisms driving α‑synuclein aggregation and disease progression. This review provides an integrated overview of PD across epidemiological, etiological, pathophysiological, and clinical dimensions. It emphasizes established and emerging risk factors, including environmental toxins, lifestyle variables, and gut microbiota dysbiosis and delineates how peripheral–central pathways such as the gut–brain, erythrocyte–brain, and kidney–brain axes contribute to PD pathogenesis. At the molecular level, we explore key disruptions including proteostatic failure, aberrant phase separation, oxidative stress, neuroinflammation, synaptic dysfunction, iron dyshomeostasis, and impaired cholesterol metabolism. These encompass microbiome‑targeted interventions and blood-based approaches. We further evaluate a spectrum of management strategies ranging from primary prevention and biomarker‑guided early detection to innovative experimental treatments such as cellular therapies, transfusion‑based modalities, and microbial modulation. By integrating recent advances in systemic pathophysiology with translational perspectives, this review highlights how molecular and cellular dysregulations underlie clinical phenotypes. Finally, we discuss promising biomarkers derived from microbial, inflammatory, and erythrocyte pathways that may facilitate early diagnosis and the development of disease‑modifying therapies.

Cellular plasticity, the ability of cells to dynamically alter their phenotypes, is a key driver of tumor evolution. This process is a hallmark of cancer which enables the acquisition of malignant traits, leading to metastasis, progression, and therapy resistance. It is governed by cell-intrinsic factors, such as genomic instability and epigenetic reprogramming, and extrinsic stimuli from the tumor microenvironment. However, a unified framework is still needed to position plasticity as the central process that links these drivers to diverse cancer hallmarks. In this review, we first explore how plasticity enables key steps of tumor evolution, including tumorigenesis, metastasis driven by epithelial–mesenchymal plasticity (EMP), therapy resistance, and cancer stem cell (CSC) dynamics. We then summarize the intrinsic and extrinsic mechanisms that govern this adaptability. Finally, we discuss clinical advances in monitoring and targeting plasticity and highlight how new spatiotemporal technologies can address current research challenges. This review provides a framework positioning cellular plasticity as a central mechanism in cancer evolution, connecting its fundamental drivers to clinical translation. By synthesizing the latest advances, we offer perspectives for developing therapies that integrate prediction, monitoring, and targeting of plasticity to proactively guide cancer evolution toward manageable outcomes.

Zona pellucida (ZP) proteins, essential for oocyte development, undergo posttranslational regulation through furin-mediated cleavage. Nevertheless, our understanding of the functional significance of furin-mediated cleavage of ZP proteins in female reproduction remains limited. Here, using mouse models with disrupted furin cleavage sites in ZP1, ZP2, and ZP3, we found that loss of the furin site in ZP2 caused female infertility associated with empty follicle syndrome (EFS), manifested by the failure to retrieve oocytes after ovarian hyperstimulation. In contrast, female mice carrying cleavage-resistant variants at the furin sites of ZP1 and ZP3 exhibited defective ZP in a subset of oocytes, leading to reduced fecundity. Mechanistically, disruption of the furin cleavage site in ZP2 impaired the transmembrane transport of the non-cleaved ZP2 protein and subsequently reduced the levels of SNARE proteins, ultimately triggering oocyte apoptosis through activation of the p53 and PI3K signaling pathways. Collectively, we uncovered the essential role of furin-mediated cleavage of ZP proteins in female fertility and provided new mechanistic insights into the pathogenesis of EFS. These findings open new avenues for investigating the contribution of posttranslational modifications to female reproduction and for developing potential therapeutic strategies to treat female infertility.

Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis, possesses notable anti-inflammatory, antioxidative, and anticancer properties. Despite its therapeutic potential, the full scope of its effects on healthspan and longevity remains unexplored. This study investigates the impact of baicalein on longevity and health-related biomarkers using the nematode Caenorhabditis elegans. Baicalein was administered to a wild-type N2 strain, seven mutant strains, and three reporter strains. Its influence on longevity, motility, lipofuscin accumulation, and oxidative stress resistance was assessed. The methodology included Kaplan–Meier survival analysis, in vivo imaging, fluorescence microscopy, and real-time PCR to evaluate RNA and protein expression. The findings indicate that baicalein significantly extends lifespan and enhances health markers, including improved motility, increased oxidative stress resistance, and reduced lipofuscin accumulation. Mechanistically, baicalein suppressed the DAF-2-mediated insulin/IGF-1 signaling pathway and promoted the nuclear translocation of DAF-16, a pivotal longevity transcription factor. Furthermore, baicalein upregulated the expression of the sod-3 gene, which is associated with enhanced stress tolerance and lifespan extension. These results elucidate the function of baicalein in promoting longevity and healthspan in C. elegans through modulation of insulin/IGF-1 signaling. Future studies are warranted to explore the applicability of baicalein in human aging to pave the way for innovative antiaging supplement formulations.

The metabolic signature of anti-leucine-rich glioma-inactivated 1 (anti-LGI1) autoimmune encephalitis remains poorly defined. We sought to delineate disease-specific ¹⁸F-FDG PET patterns and assess their relationships with clinical severity and cognition. Forty-seven patients with anti-LGI1 encephalitis and 25 healthy controls underwent ¹⁸F-FDG PET/CT, and voxel-wise comprised to identify regional metabolic alterations. A disease-specific metabolic pattern was derived with fivefold cross-validation, and a metabolic covariance network was mapped using the Brainnetome atlas. Pattern expression scores were correlated with clinical assessments. Compared to controls, patients demonstrated hypermetabolism in the hippocampal rostal, nucleus accumbens (NAc), and hypothalamus, alongside hypometabolism in the dorsolateral prefrontal cortex and posterior cingulate cortex (PCC). We identified a robust metabolic pattern centered on the NAc with extensions to the hippocampus, prefrontal cortex, and PCC; expression of this pattern correlated positively with both clinical severity and cognitive impairment. Subgroup analyses showed no significant differences in basal ganglia metabolism between patients with and without faciobrachial dystonic seizures (FBDS), or in hypothalamic metabolism between those with and without hyponatremia. Overall, ¹⁸F-FDG PET uncovers a NAc-centered metabolic network that parallels disease severity in anti-LGI1 encephalitis. Our study offers potential biomarker for clinical evaluation and provides valuable insights into the underlying pathogenesis of clinical manifestations.

Alternative splicing (AS) is an important posttranscriptional process that increases proteomic complexity of eukaryotes. Through the selective inclusion or exclusion of exons, AS fine-tunes gene expression and underpins diverse biological processes. Recent research revealed that AS is controlled not only by spliceosomal components but also by dynamic RNA structures and the spatial compartmentalization of splicing factors within biomolecular condensates formed via liquid–liquid phase separation (LLPS). Nevertheless, a unified framework connecting these mechanistic insights with emerging therapeutic strategies remains lacking. This review systematically integrates current knowledge of AS regulation, encompassing the architecture and dynamics of the core spliceosome, structural RNA elements such as G-quadruplexes, and LLPS-driven condensates exemplified by oncogenic SRSF9 droplets. It further delineates how AS influences cell development, immune modulation, and stress adaptation, while its dysregulation contributes to human pathologies, including SF3B1 mutant cancers, TDP-43-associated neurodegeneration, and cardiovascular disease. We critically appraise therapeutic innovations targeting aberrant splicing, including small molecule spliceosome modulators, antisense oligonucleotides like nusinersen, and CRISPR/dCas13-based RNA editing. By integrating molecular mechanisms with translational advances, this review provides a conceptual framework to accelerate RNA-targeted precision medicine in the era of spatial multiomics and artificial intelligence.

Efferocytosis is the fundamental mechanism by which phagocytes clear apoptotic cells to maintain tissue homeostasis. This process is also closely linked to immune tolerance, metabolic reprogramming, inflammation resolution, and tissue repair. In recent years, research spanning cardiovascular disease, autoimmune disorders, metabolic inflammation, neurodegeneration, and cancer has revealed diverse context-dependent regulatory networks, including “eat-me” and “don't-eat-me” signals, phagocytic receptors, intracellular signaling pathways, and metabolic checkpoints. Disruption of these regulatory layers contributes to the defective resolution of inflammation, persistent immune activation, and impaired tissue regeneration. However, a unified comparative framework that integrates these mechanisms across different disease states is lacking. In this review, we provide a comprehensive overview of the biology of efferocytosis, from apoptotic cell recognition and engulfment to downstream immunometabolic rewiring. We highlight disease-specific alterations in atherosclerosis, myocardial infarction, autoimmune diseases, neuroinflammation, and the tumor microenvironment. In addition, we summarize the emerging therapeutic strategies, including receptor agonists, metabolic interventions, engineered extracellular vesicles, and immune checkpoint modulation. Finally, we propose a “full-cycle” monitoring strategy that integrates imaging-based quantification, circulating biomarkers, multiomics profiling, and artificial intelligence to enable dynamic assessment of efferocytosis in vivo.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive subtype of T-ALL. Once refractory or relapsed, it is associated with a poor prognosis, with a complete remission (CR) rate of 36%–46% following re-induction therapy. Previously, we reported a synergistic effect of venetoclax (VEN) and homoharringtonine (HHT) in ETP-ALL, which potentially elicits notable clinical responses. Herein, we investigated the efficacy and safety of the V-HAG regimen (VEN, HHT, cytarabine, and granulocyte colony-stimulating factor [G-CSF]) in patients with refractory/relapsed ETP-ALL through a prospective, multicenter, single-arm, open-label, phase 2 clinical trial. A total of 18 patients were enrolled, and 100% of these patients achieved CR or CR with incomplete hematological recovery (CRi) after 1 cycle of the V-HAG regimen as re-induction therapy. As a follow-up, both the relapse rate and mortality rate were 33.3%. The 1-year overall survival and relapse-free survival were 76.7% (95% confidence interval [CI]: 53.2%-100.0%) and 55.7% (95% CI: 28.8%–82.6%), respectively. The most common grade 3–4 adverse events were neutropenia (100%), anemia (88.9%), and thrombocytopenia (100%). Notably, the VEN- and HHT-based therapy, V-HAG regimen, exhibits an extremely high efficacy in the treatment of patients with refractory/relapsed ETP-ALL with good tolerance, and it provides a promising therapeutic strategy for improving their outcomes.

Chronic otitis media with effusion (COME) is a common condition that can lead to hearing loss without acute inflammation. However, its underlying pathogenesis remains poorly understood, particularly with regard to microbial contributions. In this study, we characterized and compared the microbiota of the middle ear, nasal cavity, and oral cavity in 100 patients with COME and 77 controls using 16S rRNA gene sequencing. Alpha diversity, assessed by the Pielou index, was significantly reduced in the middle ear microbiota of COME patients compared with controls, and microbial compositions differed markedly across all sampled sites. Notably, Aeromonas, Serratia, and Lactococcus were enriched in both middle ear and nasal samples from COME patients. Among these, Aeromonas achieved the highest predictive value for COME in otic samples, whereas Lactococcus showed the strongest performance in nasal samples, with strong inter-site correlations. Functional analysis revealed the enrichment of pathways related to biofilm formation and depletion of antibiotic biosynthesis in COME-associated microbiota. These findings highlight the presence of microbial dysbiosis, particularly the interplay between nasal and middle ear microbiota, as a potential contributor to the COME pathogenesis, and suggest novel microbial targets for diagnosis and therapeutic intervention.

Poliovirus is characterized by three antigenically distinct serotypes that do not elicit cross-neutralizing antibodies. In the final stages of poliovirus eradication, the gold-standard conventional neutralization test (cNT) for detecting serum neutralizing antibodies (NAbs) is highly restricted due to biosafety concerns. To address this, we developed a high-throughput, tri-color pseudovirus-based neutralization assay (PBNA) for the simultaneous quantification of NAbs against all three poliovirus serotypes. We generated pseudoviruses by co-transfecting cells with P1 plasmids, a replication plasmid, and a T7 RNA polymerase plasmid. By optimizing P1 expression, sensitive cell selection (HEK 293T), and plasmid transfection ratios (3:3:1 for P1, replicon, and T7 plasmids), we produced high-titer pseudoviruses (>29-fold increase in titers). Based on high-titer pseudovirus encoding distinct fluorophores (E2, eGFP, and RFP), the PBNA was established, which was optimized for a 12 h incubation period, 4 × 10⁴ cells per well, and 1500 TCID₅₀/mL of pseudovirus. It demonstrated high sensitivity, strong serotype specificity, and excellent reproducibility. Furthermore, the PBNA and cNT exhibited excellent congruency (r > 0.88, all serotypes). The tri-color PBNA provides a safe, rapid, and alternative to the cNT, making it an invaluable tool for large-scale serosurveillance, novel vaccine evaluation, and fundamental virological investigations in the post-eradication era.

Complex and dynamic networks of molecules are involved in human diseases. Single-cell and spatial multiomics approaches have created new avenues for understanding the pathogenesis and diagnosis of diseases. Cell connections and characteristics in diseases may be examined more thoroughly by integration single-cell and spatial multiomics. In this paper, we first reviewed the single-cell and spatial multiomics approaches. Subsequently, the use of single-cell and spatial multiomics to comprehend the mechanisms of human diseases, such as cancer (head and neck squamous cell carcinoma), neurodegenerative diseases, and aging, was discussed. Furthermore, we outline how deep learning approaches are now being applied to single-cell and spatial multiomics data analysis in an effort to better define the pathogenic alterations upstream and the downstream molecular effects of diseases. Particularly, single-cell and spatial multiomics are being utilized to help guide treatment plans, evaluate risks, and determine how they can affect precision medicine. Despite the relative youth of the field, the development of single-cell coupled with spatial multiomics promises to provide a powerful tool for elucidating the pathogenesis of diseases.

Traditionally considered to function solely as signaling molecules within the central nervous system (CNS), neurotransmitters are now recognized as key regulators of systemic homeostasis. They modulate interactions among the nervous, immune, and metabolic systems and influence the development of various diseases. This review systematically summarizes the fundamental properties of major neurotransmitters, including their biosynthesis, receptor subtypes, and key signaling pathways, and analyzes their context-dependent roles in cancer, neurodegenerative diseases (NDDs), and inflammatory disorders. A primary focus is the three-dimensional regulatory principle that determines their effects, namely: the receptor type they bind to, cellular microenvironment, and stage of the disease. These factors explain the bidirectional effects of neurotransmitters in disease. This review also evaluates current therapeutic approaches targeting neurotransmitter pathways, ranging from receptor-specific drugs to emerging combination therapies, and discusses challenges in clinical translation, such as off-target effects of nonspecific drugs and variable efficacy across disease types. By linking the fundamental mechanisms of neurotransmitter function to clinical challenges, this review provides a comprehensive framework for exploiting the neurotransmitter–immune axis to develop precise therapeutic strategies aimed at improving outcomes in cancer, NDDs, and inflammatory disorders.

Influenza, a highly pathogenic infectious disease, causes nearly half a million deaths annually worldwide. Thus, effective vaccine-based prevention and control are crucial. Although live attenuated influenza vaccines (LAIVs) can induce mucosal immunity, existing vaccines effectiveness remains relatively low, posing a significant threat to public health. Thus, we developed a novel mosaic H1N1 LAIV candidate by integrating mosaic antigen design with established LAIV technology. This vaccine incorporates most potential T-cell epitopes of hemagglutinin and neuraminidase antigens into an attenuated master donor strain, ensuring safety and broad immunity. We compared it with commercial monovalent attenuated and inactivated vaccines in mice. The mosaic H1N1 LAIV induced robust cross-reactive humoral and mucosal immune responses, enhanced antigen-specific cellular immunity, and established tissue-resident memory T and B cells in the respiratory tract. Challenge experiments confirmed its protective efficacy against homologous and heterologous strains. It provided complete protection against homologous strains with low epitope similarity and partial protection against the ancestral H3N2 virus. Our study highlights the mosaic H1N1 LAIV as an excellent universal vaccine candidate capable of inducing broad cross-reactive immune responses and providing robust protection against distinct influenza A viruses, demonstrating a promising strategy to address the limitations of current commercial vaccines.

Stroke can be classified into ischemic stroke (IS), hemorrhagic stroke (HS), and subarachnoid hemorrhage. The high incidence, disability, and mortality rates, especially from IS, place a huge burden on global health. The pathophysiological processes following IS mainly involve energy deficiency, ion homeostasis imbalance, oxidative stress, neuroinflammation, programmed cell death, blood–brain barrier disruption, and cerebral edema. Transient ischemic attack is an early warning sign of IS, characterized by temporary neurological deficits. HS mainly involves primary damage caused by the mass effect of hematoma and secondary damage caused by the toxic components of hematoma. Although advances in acute-phase reperfusion technology have reduced mortality, the fundamental challenge of a narrow therapeutic window limits patient eligibility and long-term recovery outcomes. This review aims to provide a comprehensive overview of stroke, detailing its epidemiology, risk factors, pathophysiological mechanisms, signaling pathways, and clinical management methods. Here, we focus on the latest research progress in IS and emphasize the hope that regenerative therapies, especially stem cell therapies, offer for stroke patients. This review aims to provide a detailed overview of current research and clinical practice in stroke, propose emerging strategies for treating stroke patients, and provide an outlook on future research directions in this field.