Adenosine-to-inosine (A-to-I) RNA editing, predominantly catalyzed by the enzyme adenosine deaminase acting on RNA 1 (ADAR1), has attracted interest due to its essential functions in regulating immune response and cancer progression. This research investigates ADAR1 inhibition as a promising strategy aimed at improving immunotherapy efficacy in lung adenocarcinoma (LUAD) and explores the underlying mechanisms. Findings from murine models demonstrate that ADAR1 suppression within tumors notably improves the immune microenvironment, marked by increased PD-L1 expression and enhanced CD8⁺ T-cell infiltration, as well as elevated levels of CXCL9, CXCL10, and CXCL11. These changes promote antitumor T-cell immune responses and amplify the effects of immunotherapy. Mechanistic investigations further reveal that deficiency in ADAR1 leads to an increase in double-stranded RNA (dsRNA), which serves as a substrate for A-to-I editing. This activates downstream signaling via dsRNA receptors, including RIG-I and MAVS, thereby inducing the IFN-β pathway. Significantly, IFN-β contributes to the ADAR1-dependent modulation of the tumor immune microenvironment and carcinogenesis in LUAD. Clinical validation in LUAD patients further confirms that reduced ADAR1 expression is associated with improved immunotherapy responses. These findings suggest inhibiting ADAR1-mediated A-to-I RNA editing is a promising approach to enhance the efficacy of immunotherapy in LUAD.

Efficient detection of breathing impairment is critical for treatment and prognosis in neuromuscular disorders. However, standard pulmonary function tests often yield ambiguous results. This prospective study evaluates whether advanced real-time MRI (RT-MRI) combined with deep learning-based image segmentation provides sensitive outcome measures for respiratory dysfunction in late-onset Pompe disease (LOPD), a model disease for diaphragmatic weakness. Eleven Pompe patients (mean age 52.2 years; 55% female) and 11 controls (mean age 50.9 years; 55% female) were included. RT-MRI with a temporal resolution of 50 ms, combined with U-Net-supported lung segmentation, revealed significantly reduced diaphragmatic motion in Pompe patients compared to controls and unmasked paradoxical diaphragmatic motion in Pompe patients (7 of 11). Reduced diaphragmatic sniff velocity and pathological diaphragmatic/thoracic synchronicity were detected in Pompe patients with still normal results in standard pulmonary function tests. Fatty involution of the diaphragm as quantified by fast T1 mapping correlated significantly with functional parameters from RT-MRI and pulmonary function tests. RT-MRI combined with deep learning-based lung segmentation offers novel biomarkers for early detection of respiratory muscle weakness. This new technique provides useful outcome measures for clinical care as well as treatment studies in patients with neuromuscular breathing impairment. The technique can also be used to characterize physiologic breathing patterns in healthy individuals.

Cancer is a global health challenge. The initiation and progression of cancer are correlated with dynamic dysregulation of RNA regulatory networks. This review systematically explains how contending RNAs (including mRNA, miRNA, lncRNA, circRNA, etc.) remold gene expression programs across multiple dimensions. They do this primarily through the competing endogenous RNA sponge effect, RNA–protein complex assembly, RNA editing (A-to-I editing, m6A modification, etc.), tumorigenesis, heterogeneous evolution, and therapeutic resistance. RNA regulatory networks do not only help one to decode cancer biology but because they are dynamic in nature, they are now also being looked at as good precision targets for diagnosis and treatment. This article integrates recent findings on the emerging functions of RNA networks in tumor metabolic reprogramming, tumor immune microenvironment shaping, and cancer stem cell property maintenance, while highlighting their clinical application prospects as liquid biopsy biomarkers. Our therapies focus on assessing the potential and clinical translation bottlenecks of novel RNA-targeted interventions, including antisense oligonucleotides, RNA aptamers, and the CRISPR–Cas13 system. A dynamic adjustability made the RNA-targeted therapies promising intervention nodes in precision medicine even if most of them are still in a preclinical state.

Artificial intelligence (AI) is catalyzing a paradigm shift in medical robotics, transforming medical robots from teleoperated tools into intelligent partners across clinical domains. This evolution is pivotal in addressing global challenges like aging populations, driven by core AI pillars—including computer vision (CV), deep reinforcement learning, and large language models (LLMs)—that support perception, decision-making, and naturalistic communication, enabling varying degrees of autonomy and adaptive care. However, the literature still lacks a holistic analysis that integrates these advances and tackles the translational challenges hindering clinical adoption. This review bridges this gap by systematically charting the evolution of AI-driven robotics across intelligent surgery, adaptive rehabilitation, and multimodal healthcare delivery. We dissect the core technologies powering this revolution, from digital twins for surgical simulation to LLMs for enhanced human–robot interaction, and critically analyze the associated technical, ethical, and regulatory hurdles. By synthesizing current progress and outlining future frontiers, including embodied AI, nanorobotics, and the concept of the AI-augmented surgeon, this review provides a comprehensive roadmap for accelerating the translation of intelligent medical robotics into routine clinical practice.

The LKB1–AMPK signaling pathway is a master regulator of cellular energy homeostasis and a central hub in stress adaptation. As a conserved metabolic sensor, this pathway coordinates glucose, lipid, and protein metabolism, thereby sustaining physiological function across diverse tissues. Beyond its canonical role in energy balance, growing evidence highlights its dysregulation in multiple pathological conditions. Despite extensive mechanistic studies, the disease-specific regulation and translational potential of the LKB1–AMPK pathway remain incompletely understood. This review systematically studies the molecular basis and regulatory mechanisms of LKB1–AMPK signaling in cardiovascular diseases—including atrial fibrillation, ventricular fibrillation, myocardial infarction, cardiac hypertrophy, heart failure, and atherosclerosis—where impaired pathway activity underlies energy deficits, fibrosis, oxidative stress, and arrhythmogenesis. We further explore its involvement in metabolic disorders such as diabetes and diabetic nephropathy, in neurodegenerative diseases like Alzheimer's and Parkinson's disease, and in oncology, where LKB1 mutations drive tumorigenesis and alter therapeutic responses. Emerging strategies, including metformin, novel AMPK activators, and LKB1-based gene therapies, are highlighted as promising yet challenged by tissue specificity, off-target effects, and genetic variation. By integrating insights from cardiovascular, metabolic, neurological, and oncological research, this review underscores the pathway's potential as both a biomarker source and therapeutic target, providing a foundation for precision medicine in complex diseases.

Cerebral venous outflow insufficiency (CVOI) is a recently recognized cerebrovascular condition characterized by impaired venous drainage from the brain to the extracranial system. However, its clinical phenotypes and classification criteria remain poorly defined. In this single-center cross-sectional study, we analyzed 245 patients with CVOI using contrast-enhanced CT or MR venography to identify clinical features and propose a novel anatomical classification. We identified 10 major symptoms of cerebral venous congestion, with tinnitus cerebri, neck discomfort, and tinnitus being the most common. A new classification system was proposed based on lesion location and bilateral jugular foramen narrowing rate, categorizing CVOI into intracranial (CV), extracranial (JV), and tandem (CJV) types, each further stratified into four/five subtypes. Receiver operating characteristic (ROC) curve analysis showed that narrowing thresholds of 0.20 and 0.40 offered excellent discriminatory performance for subtype differentiation, with an area under the curve (AUC) approaching 1.0. Notably, tandem-type CVOI (CJV) was the most prevalent (56.7%) and exhibited distinct symptom patterns and pathogenesis. These findings provide a practical framework for diagnosing and stratifying CVOI and may inform individualized treatment strategies.

Heart failure (HF) is one of the leading causes of hospitalization and mortality worldwide. Despite continuous updates to modern clinical guidelines regarding HF classification and management, mortality and rehospitalization rates remain persistently high. Enhancing the prevention and treatment of HF therefore represents a major challenge both now and in the future. In this review, we synthesize HF epidemiology and systematically mapped the calcium‑handling differences under physiological and pathological conditions, as well as the patterns of calcium‑homeostasis dysregulation across the major HF subtypes (heart failure with reduced ejection fraction; heart failure with preserved ejection fraction). Moreover, we summarize alterations in key calcium-regulating proteins (points) and calcium homeostasis-related pathways (lines), and further integrate these nodes into a network model that links Ca²⁺ dynamics remodeling with inflammation, oxidative stress, and mitochondrial dysfunction. Building on this mechanistic network, we discuss both conventional HF management strategies and emerging therapeutic developments that target distinct mechanisms through points and lines. Finally, we outline the unmet needs and future directions across the current “diagnosis–treatment–monitoring” continuum, with the overarching goal of advancing precision diagnosis, individualized therapy, and the establishment of a comprehensive HF management framework.

Hemidesmosomes are structures that anchor junctions between basal epithelial cells and the basement membrane, essential for skin integrity. Genetic mutation of hemidesmosomes was well documented for the inherited bullous disorder, but is rarely investigated for acquired bullous disorders. We designed a 16-gene targeted capture panel and sequenced 202 patients with hemidesmosomes-related acquired disorders and 123 healthy controls, identifying 114 pathogenic variants in 15 genes, including 20.2% novel variants. Clinical relevance (disease severity and outcome) and immunohistochemistry results demonstrated that ITGA6, LAMC2, and EPPK1 mutations significantly affected the expression of hemidesmosome-related proteins, compared with controls with non-carriers. Functional studies in Caenorhabditis elegans models with transmission electron microscopy and confocal microscopy demonstrated that ITGA6 (ina-1) mutation can disrupt the hemidesmosomes assembly network, such as cytolinker (vab-10a) and apical (mup-4) and basal (let-805), thereby disrupting the hemidesmosome structure. This represents a quantitative to qualitative change in pemphigoid disease. Transcriptomic and serum proteomic analyses further revealed that ITGA6 mutations perturb epithelial development and hemidesmosome integrity, with both missense/loss-of-function variants leading to activation of NOD-like receptor–NF-κB–TNF–pyroptosis signaling pathways. These findings highlight the critical role of hemidesmosome genetic variants in the development of not only inherited but also acquired autoimmune bullous disorders.

Bipolar disorder (BD) research confronts challenges: blood-based biomarkers offer limited insights into neurobiology, while cerebrospinal fluid (CSF) collection is clinically unusual. Linking genetic susceptibility to pathophysiology remains crucial for biologically informed risk stratification. We integrated cohort data and genome-wide association study (GWAS) summary statistics: the largest BD meta-analysis, CSF multi-omics profiles including 3107 proteomic and 2602 metabolomic participants, and a validation cohort of 247,834 UK Biobank participants. Unsupervised clustering revealed four single-nucleotide variant (SNV) clusters: metabolic-imbalance, metabolic-active, human leukocyte antigen (HLA)+immune, and HLA-immune. These clusters exhibited distinct clinical features, with the metabolic-imbalance cluster showing multi-directional associations with 21 psychiatric traits, while the HLA-immune cluster was associated with emotional instability in BD patients (odds ratio [OR] = 1.14, p = 0.027). The optimized multimodal cluster-specific polygenic risk scores (PRS) model significantly outperformed clinical-only prediction factors (C-index = 0.77), with the metabolic-imbalance PRS contributing a 22.6% incremental predictive value (hazard ratio [HR] = 1.23, 95% CI: 1.04–1.45, p = 0.016). Risk reclassification showed an 84% reduction in false-negative rates in the low-risk subgroup, identifying a high-risk layer with a 17.6-fold increased BD incidence. Altogether, genetically informed substitutes for CSF biomarkers emerged as a scalable tool for risk prediction, overcoming the barriers of CSF collection while capturing neurobiological heterogeneity.

Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers and is an important target for cancer therapy. In this study, HS1002 was synthesized based on the amino acid sequences of gonadotropin-releasing hormone (GnRH) and hTERT. This study aimed to evaluate HS1002's anticancer activity and its effects on the gonadotropin-releasing hormone receptor (GnRHR) and hTERT in prostate cancer cells. HS1002 increased cytosolic calcium influx in GnRHR-overexpressing HEK293 cells and showed specific molecular docking interactions with GnRHR. Compared with prostate cancer cell lines, HS1002 exhibited the highest cytotoxicity against LNCaP cells. The hTERT expression correlated with telomerase activity was suppressed by HS1002, resulting in reduced metastasis and increased apoptosis and autophagy. Additionally, HS1002 suppressed c-Myc and ERK protein expressions in LNCaP cells. Furthermore, HS1002 inhibited tumor growth and downregulated hTERT expression in the xenograft model tumor tissues. HS1002/IL-2-pretreated PBMCs also exhibited potent cytotoxicity toward LNCaP cells. In addition, HS1002 increased the production of granzyme B and IFN-γ in CD8⁺ T cells in MC38 syngeneic mice. These findings demonstrate that HS1002 suppresses prostate cancer cell growth and induces anticancer immunity, suggesting its potential as a novel therapeutic agent against prostate cancer.

In the HOMAGE (Heart Omics in AGEing) trial, spironolactone reduced serum concentrations of procollagen Type I C-terminal propeptide (PICP), a fibrosis biomarker, in patients at risk of heart failure. To elucidate the underlying mechanisms, multidimensional analyses including proteomics were conducted. Olink cardiovascular and inflammation panels (n = 276 proteins) were measured in plasma from 488 HOMAGE participants at baseline, 1 month, and 9 months after randomization. Proteins associated with PICP changes were identified using machine learning algorithms (MLAs). Selected candidates were further analyzed in patients with heart failure and preserved ejection fraction (Aldo-DHF trial). Linear regression and mediation analyses assessed which MLA-selected proteins mediated spironolactone's effects on PICP. MLAs consistently linked PICP reduction to changes in biomarkers of collagen (e.g., decreased COL1A1), fatty acid metabolism (e.g., increased FABP4), immune function (e.g., increased CCL24 and IL6RA, and decreased FLT3L), neurological function (e.g., increased DNER), cell–matrix interactions (e.g., increased galectin-9 [GAL9] and decreased thrombospondin-2 [THBS2]), and reduced NT-proBNP. Mediation analysis suggested that changes in GAL9 and THBS2 were associated with spironolactone-induced PICP reduction, which was confirmed in Aldo-DHF patients. This study raises the hypothesis that spironolactone inhibits collagen synthesis via inflammatory, metabolic, and extracellular matrix pathways, and particularly through modulation of GAL9 and THBS2.

Immune exhaustion is a state of sustained lymphocyte dysfunction that occurs following chronic antigenic stimulation and constitutes a shared hallmark of chronic infection and cancer. Beyond being a passive consequence of persistent antigen exposure, it actively drives tumor progression by fostering immunosuppressive microenvironments. Pathogens that evade immune detection to establish chronic infection can directly induce immune exhaustion through sustained inflammatory signaling, thereby crippling cytotoxic T cell-mediated tumor surveillance. This impairment facilitates both de novo tumorigenesis and the aggressive evolution of pre-existing malignancies. This comprehensive review delineates the mechanisms and characteristics of immune exhaustion within the contexts of chronic infection and cancer, as well as its impact on disease progression. Furthermore, we propose a chronic infection–exhaustion–tumor axis and analyze this pathway with reference to specific pathogens. Finally, we provide a critical appraisal of current strategies designed to reverse immune exhaustion and discuss their therapeutic potential and limitations within three defined contexts: chronic infection, cancer, and the interplay between chronic infection and tumor development. By integrating insights from virology and immuno-oncology, this work proposes therapeutic strategies to disrupt the infection–exhaustion–tumor axis, offering a roadmap for precision oncology.

Companion diagnostics (CDx) plays a pivotal role in precision medicine by enabling personalized treatment plans based on individual biomarker profiles. This approach can enhance therapeutic efficacy in selected indications and may reduce healthcare expenditures. Particularly in oncology, precision targeted therapies targeting pathways such as EGFR, HER2, and programmed death-1/programmed death-ligand 1 have established robust models for biomarker-driven treatment. However, rapid advancements in diagnostic technologies, expanding application scopes, and increasingly complex mechanisms of biomarker resistance are presenting new challenges for CDx. This review comprehensively examines the evolving regulatory landscape, current clinical applications across various solid tumors and hematologic malignancies, and diverse methodological platforms ranging from next-generation sequencing and immunohistochemistry to emerging liquid biopsies and point-of-care testing. It also delves into persistent barriers in CDx development, including tumor heterogeneity, test standardization, trade-offs between tissue biopsy and liquid biopsy, and the economic complexities of codevelopment and reimbursement mechanisms. By synthesizing existing knowledge and projecting future trends, this paper serves as a valuable resource for researchers, regulators, and clinicians. It provides critical insights to guide the synergistic development of drugs and diagnostics, paving the way for their integration into a more dynamic, artificial intelligence-enhanced, and multiomics-driven healthcare ecosystem.

Clear cell renal cell carcinoma (ccRCC) accounts for 70%‒80% of renal cell carcinoma cases and often shows no symptoms in early stages. Thus, approximately 30% of patients are diagnosed with advanced ccRCC. This single-center prospective single-arm study evaluated the efficacy and safety of tislelizumab combined with axitinib in patients with locally advanced ccRCC. A total of 20 eligible patients were enrolled at Nanjing Drum Tower Hospital from September 2021 to June 2024. The primary endpoint was objective response rate (ORR) before surgery, and secondary endpoints included disease-free survival (DFS), overall survival, safety, and tissue biomarker analysis. All patients completed neoadjuvant treatment, and 19 underwent planned surgery; 70% (14/20) had cT3 stage disease with a median tumor diameter of 8.3 cm. The ORR was 55% (11 partial responses), 73.6% (14/19) achieved pathological downstaging, one patient attained pathological complete response, and no grade ≥3 perioperative complications occurred. The 2-year DFS rate was approximately 90%, and biomarker analysis showed significantly higher tumor shrinkage rates in patients with RTK/RAS pathway alterations. In conclusion, tislelizumab combined with axitinib exhibits substantial efficacy and acceptable safety in neoadjuvant treatment of locally advanced ccRCC, providing preliminary clinical evidence for its application.

Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome that poses challenges for therapeutic development and contributes to suboptimal patient outcomes. The phenotypic classification of patients with HFpEF to guide etiology-specific therapeutic strategies represents a rational approach to address the current dilemma. However, the clinical outcomes of HFpEF under different etiological classifications remain poorly understood. Here, we assessed the clinical outcomes of HFpEF patients across different etiological phenotypes, based on a novel classification system comprising five categories: vascular-related, cardiomyopathy-related, right heart/pulmonary-related, valvular/rhythm-related, and extracardiac disease-related HFpEF. Data from the Chinese Cardiovascular Association Database-Heart Failure Center Registry (2017–2021) were analyzed, including 51,466 hospitalized HFpEF patients with 1-year follow-up. Significant differences in baseline characteristics and clinical outcomes were observed among phenotypes. Patients with right heart/pulmonary-related, valvular/rhythm-related, and extracardiac disease-related HFpEF showed a higher incidence of adverse outcomes. Specifically, the right heart/pulmonary-related and valvular/rhythm-related phenotypes were associated with increased heart failure rehospitalization, while extracardiac disease-related HFpEF was linked to higher cardiovascular mortality. Prognostic risk factors also varied across phenotypes. In conclusion, 1-year outcomes exhibit significant variations across HFpEF phenotypic subgroups. Future studies should explore whether phenotype-specific personalized treatment strategies can improve clinical outcomes, especially in high-risk phenotypes.

Electrical stimulation is a common technique in neuroscience and clinical therapies, with stimulation frequency being a critical factor in its efficacy. However, the cellular mechanisms by which different frequencies of pulsed electrical stimulation modulate neuronal activity remain poorly understood. In this study, we explore the effects of 60 Hz (low frequency [LF]) and 160 Hz (high frequency [HF]) pulsed electrical stimulation on excitatory and inhibitory neurons in the primary somatosensory cortex (S1) of mice using two-photon Ca²⁺ imaging. Our results show that HF stimulation significantly increased Ca²⁺ activity in excitatory neurons in layer 2/3, both during and after stimulation, while LF stimulation enhanced neuronal activity only post-stimulation. In layer 5 excitatory neurons, HF stimulation increased neuronal activity only after stimulation cessation, whereas LF stimulation transiently suppressed activity during stimulation. Both LF and HF stimulation enhanced activity in inhibitory neurons in layer 2/3 during stimulation. In summary, our study reveals that electrical stimulation activates both excitatory and inhibitory neurons, with its primary mechanism of action being the modulation of neuronal rhythm rather than the amplitude of their activity. These findings shed light on stimulation mechanisms, supporting its therapeutic potential for neuropsychiatric disorders targeting neuronal rhythmicity.

Antimicrobial resistance represents a significant global health threat, demanding alternative treatments beyond traditional antibiotics. Phage therapy has resurged as a promising solution to address this challenge. This manuscript offers an in-depth examination of phage applications in clinical settings, encompassing the treatment of multidrug-resistant infections, prevention of hospital-acquired infections, and development of phage-based vaccines. Advanced strategies are explored, including phage–antibiotic synergy, biomaterial-enhanced delivery systems to improve phage stability, and the rational design of engineered phages to expand host range and optimize lytic efficacy. Additionally, the application of genetic engineering to broaden phage host ranges and convert temperate phages into lytic variants is discussed. In hospital infection prevention, phages demonstrate substantial potential, such as eliminating bacterial biofilms on medical devices, disinfecting environmental surfaces, and controlling waterborne pathogens in hospital water systems. Furthermore, phages offer a versatile platform for vaccine development, facilitating efficient antigen display and nucleic acid delivery. Despite progress, challenges persist in pharmacokinetics, standardized production, and regulatory approval. This review synthesizes recent preclinical and clinical developments, emphasizing the transformative potential of phage-based therapies while acknowledging the barriers to their clinical implementation.

Atherosclerotic cardiovascular diseases (ASCVDs) remain the primary cause of morbidity and mortality. Macrophages are involved in the progression and regression of atherosclerosis, and macrophage amino acid metabolism is important during this process. Here, we identified that the expression of cystine/glutamate antiporter Slc7a11 was upregulated by oxidized low-density lipoprotein, and specifically enhanced in the macrophages of atherosclerotic plaques. Macrophage-specific Slc7a11 overexpression in ApoE null mice (ApoE^–/–Slc7a11^MOE) attenuated atherosclerotic lesions and increased the plaque stability under a 16-week western diet. ApoE^–/–Slc7a11^MOE displayed unchanged blood lipids, decreased inflammatory cytokines, and increased antioxidant capacity. Mechanistically, Slc7a11-mediated cystine uptake and glutathione synthesis inhibited the classically activated macrophage (M1) polarization via reducing Stat1 phosphorylation, and promoted alternatively activated macrophage (M2) polarization via enhancing Stat6 phosphorylation. Macrophage-targeting lipid nanoparticles loading with ferrostatin-1, an antioxidant reagent, promotes Slc7a11-mediated glutathione synthesis, also enhanced plaque stability and ameliorated the progression of atherosclerosis. These findings reveal a critical role of Slc7a11 in the phenotypic switch of macrophage and indicate that Slc7a11-mediated amino acid metabolism could be utilized as a novel therapeutic strategy in the prevention of ASCVDs.

Despite the remarkable therapeutic advances achieved with immune checkpoint inhibitors in advanced melanoma, treatment options remain limited for patients with refractory subtypes. This study evaluated a novel combination of DNV3 (anti-LAG-3), toripalimab (anti-PD-1), and chemotherapy (nab-paclitaxel/cisplatin) in 27 Asian patients with unresectable or metastatic melanoma (77.8% [21/27] previously treated with anti-PD-[L]1 and 22.2% [6/27] treatment-naïve mucosal melanoma; subtypes: 13 mucosal, 6 acral, 5 cutaneous, and 3 of unknown primary origin). The regimen achieved an overall response rate (ORR) of 44.4%, which was further elevated to 54.5% in the subgroup of 11 patients with hepatic metastases. Notably, it also demonstrated substantial efficacy in anti-PD-(L)1-resistant cases, with a 42.9% ORR and a median progression-free survival (PFS) of 7.36 months. Among treatment-naïve mucosal melanoma, the ORR reached 50%. At data cutoff, median overall survival remained unreached in all cohorts. Grade ≥3 treatment-related adverse events initially occurred in 55.6% of participants; subsequent dose modification of nab-paclitaxel (from 260 mg/m² to 200 mg/m²) improved tolerability, reducing the incidence of grade ≥3 events to 22.2%. Immune-related toxicities (grade 3–4, 22.2%) were clinically manageable. Therefore, the combination of LAG-3/PD-1 blockade and chemotherapy demonstrated promising efficacy, notably in treatment-naïve mucosal melanoma with liver metastases. (Chinese Clinical Trial Registry number, ChiCTR2400079543)

Body mass index (BMI) is traditionally used to diagnose overweight and obesity, but it is influenced by physiological variables. This study tested the hypothesis that body weight is nonlinearly related to age and height, and that an optimized multivariate allometric model (OMAM) could correct for these effects and define a new criterion for overweight diagnosis. A total of 1498 Chinese Han adults were enrolled. The normal weight group (BMI < 25.0 kg/m², n = 1224) was divided into subgroup A (n = 857) to develop OMAM equations and determine the threshold, and subgroup B (n = 367) to validate them. The overweight group (BMI ≥ 25.0 kg/m², n = 274) was used to test the new criterion. OMAM corrected the nonlinear influence of age, height, and sex on weight. A corrected weight value W_C>1.1440 was defined as the new threshold. This criterion reclassified 21.9% of overweight individuals as normal weight and reduced false positives, notably lowering the overweight rate to 61.3% in men, while minimizing unnecessary interventions. Compared with BMI, the new criterion showed higher specificity and accuracy in identifying diabetes, hypertension, coronary heart disease, and metabolic syndrome in the external CAPITAL cohort. These findings support the clinical utility of OMAM in overweight screening. Further validation in non-Chinese Han populations is warranted.

Dysthyroid optic neuropathy (DON) is the most severe complication of thyroid-associated ophthalmopathy (TAO). Although recent evidence indicates that reduced retinal capillary density (RCD) may increase DON risk independently of orbital apex crowding, the underlying mechanisms and associated metabolic reprogramming remain unclear. In a retrospective analysis of TAO patients with and without DON, those with DON demonstrated elevated pulse pressure (PP), decreased RCD, and higher incidences of dyslipidemia, hyperglycemia, and internal carotid artery calcification. To explore the metabolic basis of these findings, untargeted and targeted metabolomic profiling of plasma from TAO patients and healthy controls was conducted, identifying DON-associated abnormalities in the L-arginine metabolic pathway (registration number: ChiCTR2000035598). Integrating these results with existing literature suggests that oxidative stress drives dysregulated L-arginine–nitric oxide (NO) metabolism, contributing to progressive RCD loss. In early-stage DON patients treated with oral L-arginine, improvements in RCD, PP, and visual function were observed (registration number: ChiCTR2300076962). Further analyses implicated reduced NO bioavailability, due to L-arginine depletion and endothelial NO synthase (eNOS) uncoupling, as a key contributor to declining RCD. Given that oral L-arginine can improve PP via NO-mediated pathways in cardiovascular disease, our findings offer a promising new therapeutic direction for DON management.

Late-stage cancer diagnosis and limited treatment options for advanced disease remain major contributors to cancer-related morbidity and mortality. Blood-based multicancer early detection (MCED) assays have consequently gained momentum as a means to shift diagnosis toward earlier, more curable stages. Despite their promise, substantial methodological, clinical, and implementation barriers hinder widespread adoption. Integrative approaches coupling multi-omics profiling with advanced molecular imaging may improve detection accuracy and tumor localization, while risk-adapted MCED paradigms could support more targeted, individualized screening strategies.

This article reviews the current landscape of MCED technologies, with a primary focus on circulating cell-free DNA and circulating tumor DNA–based assays, and critically evaluates their developmental status, strengths, and limitations relative to established single-cancer screening methods. The contribution of artificial intelligence, particularly advanced deep learning, to improving sensitivity, specificity, and predictive performance is discussed. The potential of MCED assays to detect aggressive, currently unscreened malignancies and to address the unique challenges of pediatric cancers is examined. In addition, emerging alternative detection strategies, ongoing clinical validation efforts, regulatory requirements, and implementation considerations are reviewed. Finally, the impact of MCED testing on cancer mortality, quality of life, and healthcare systems is outlined, along with key technological trends shaping future development and clinical translation.

The growing emphasis on precision medicine in the management of solid tumors has underscored the limitations of traditional diagnostic approaches, which often lack sufficient sensitivity or rely on invasive procedures. In contrast, peripheral blood biomarkers provide a minimally invasive, dynamic, and potentially more accurate means for cancer detection and monitoring. The enhancement of detection technology has enabled the incorporation of an increasing number of biomarkers into exploratory clinical trials, which, in turn, have demonstrated immense clinical utility. However, numerous hurdles remain before these biomarkers can be applied in a real clinical setting. This review comprehensively summarizes the clinical utility of key blood-based biomarkers, including circulating tumor cells, circulating tumor DNA, extracellular vesicles, cell-free RNA, peripheral blood mononuclear cells, and proteins. We discuss their biological characteristics, detection methodologies, and recent advances in their clinical applications. Moreover, we highlight the emerging role of new technologies such as artificial intelligence (AI) in decoding complex data and facilitating clinical decision-making. It is expected to establish the overarching concept of the blood biomarker panel and to understand its comparative advantages, which are essential to realize its potential in precision oncology.

Cancer remains a major therapeutic challenge owing to its complex pathogenesis and the limitations of current treatments, such as poor specificity, toxicity, and multidrug resistance. Chromatin accessibility, which is dynamically regulated by genetic, epigenetic, and environmental factors, plays crucial roles in cancer initiation and progression. However, substantial obstacles persist in developing therapeutic strategies that target chromatin accessibility and translating them into clinical practice. This review comprehensively summarizes the biological functions and regulatory mechanisms of chromatin accessibility in tumors, encompassing tumorigenesis, progression, metabolic reprogramming, angiogenesis, stemness, tumor immune microenvironment, and therapy resistance. We integrate comparisons between human and murine models and detail key profiling technologies, including Assay for Transposase‑Accessible Chromatin with high‑throughput sequencing, DNase‑seq, single‑cell multiomics, and three-dimensional chromatin‑conformation assays. Furthermore, we compile recent preclinical and clinical trials that utilize chromatin accessibility as a biomarker or therapeutic target, along with combination strategies involving chemotherapy, immunotherapy, targeted therapy, and radiotherapy. From a multiomics and interdisciplinary perspective, we discuss current limitations in translating fundamental research into clinical applications and highlight future directions for epigenetics‑based precision oncology.

Chemotherapy is the mainstay in the treatment of advanced gastric cancer (GC); yet, GC showed diverse responses to first-line chemotherapy regimens and the underlying molecular basis is still not clear. Here, we established a system that combined organoid-based chemotherapy regimen screening and transcriptome-based evaluation to identify underlying molecular signatures of different responses to chemotherapy. We generated 19 GC patient-derived organoids (PDOs) from surgically resected specimens with corresponding histological characteristics of parent tumors and tested all of the five most commonly used first-line chemotherapy regimens. Based on the treatment responses, PDOs were classified into double-sensitive, single-sensitive, and not-sensitive groups. PDOs that responded well to chemotherapy presented high expression levels of the P53 pathway genes and low expression levels of cell proliferative activity genes. Furthermore, the chemotherapy-based tumor classification of GC was established. The GC tumor classification was verified by multi-omics features from the TCGA dataset and public drug response datasets. In conclusion, this study systematically evaluated clinical chemotherapy regimens for GC and identified chemotherapy response-associated molecular signatures based on human GC organoids, which are beneficial to the precise treatments of GC.

Platinum resistance remains a clinical challenge in ovarian cancer. Ascites represents an important mediator and a unique tumor microenvironment (TME) for invasion and metastasis. This study performed high-resolution mass spectrometry (MS) on pre-chemotherapy ascites cells from ovarian cancer patients. Integrating proteomic profiling, clinical data, and single-cell analysis revealed that platinum-resistant ascites displayed a distinct microenvironmental: the macropinocytosis-related protein Src homology 3 domain-containing YSC84-like 1 (SH3YL1) was upregulated, whereas the immune-activation marker CD44 was downregulated in resistant cases. Single-cell analyses and pathway enrichment indicated immune exhaustion in resistant ascites, alongside enhanced macropinocytosis and lipid catabolism in tumor cells. Clinical data also showed that resistant ascites are lipid-rich, with immunofluorescence plus flow cytometry confirming its association with immune exhaustion. Cellular experiments confirmed that SH3YL1-mediated macropinocytosis promoted lipid uptake, and its inhibition partially restored cisplatin sensitivity. A combined model of immune exhaustion, macropinocytosis, and lipid catabolism suggests these ascites-associated features could somewhat predict the platinum sensitivity in ovarian cancer tissues. We therefore propose the hypothesis that, in a lipid-rich ascites microenvironment, immune exhaustion occurs while tumor cells activate macropinocytosis and lipid catabolism—forming a network of resistance mechanisms that may serve as potential predictive markers or intervention targets for platinum resistance.

The NLRP3 inflammasome is a pivotal signaling platform of the innate immune system that senses a broad spectrum of microbial, metabolic, and environmental danger signals. Its activation leads to the recruitment of ASC and caspase-1, driving the maturation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as the execution of pyroptosis. Aberrant or persistent activation of NLRP3 has been implicated in the pathogenesis of numerous disorders, including autoinflammatory syndromes, metabolic and cardiovascular diseases, neurodegenerative conditions, and cancers. In this review, we provide an updated overview of the molecular mechanisms governing NLRP3 activation and regulation, with particular focus on ion flux, mitochondrial damage, lysosomal rupture, reactive oxygen species, and post-translational modifications. We further discuss negative regulatory pathways that maintain inflammasome homeostasis and prevent excessive inflammation. Finally, we summarize recent advances in therapeutic strategies targeting the NLRP3 inflammasome, ranging from direct inhibitors and allosteric modulators to biologics and repurposed drugs, and highlight their translational potential. Understanding the fine balance between NLRP3 activation and inhibition offers new opportunities for therapeutic intervention in a wide array of inflammatory and immune-related diseases.

Varicella zoster virus (VZV) is a ubiquitous human herpesvirus that establishes lifelong latency and causes herpes zoster (HZ) upon reactivation, posing a growing clinical challenge in aging populations. The incidence of HZ increases sharply with age and immunocompromised states, and its clinical burden extends well beyond cutaneous disease to include postherpetic neuralgia, neurological complications, and systemic involvement. At the mechanistic level, HZ reflects a dynamic interplay between viral reactivation, host immune surveillance, and virus-induced neuronal injury. Despite substantial progress in antiviral therapy and vaccination, many interventions remain focused on individual stages of the disease process, and the translation of molecular insights into comprehensive clinical strategies remains incomplete. In this review, we synthesize current knowledge of VZV epidemiology, structure, and life cycle, and provide an integrated overview of clinical manifestations and molecular pathogenesis, with particular emphasis on latency, reactivation, and immune evasion. We further summarize advances in diagnostic technologies and discuss therapeutic strategies targeting viral replication, inflammatory complications, and long-term sequelae, alongside preventive approaches. By linking disease mechanisms with clinical management, this review highlights key challenges and emerging directions for improving the prevention and treatment of HZ and provides a framework for translating fundamental discoveries into more effective interventions.

FBXW7 (F-box and WD repeat domain-containing 7) is a classic tumor suppressor that promotes ubiquitylation and degradation of various oncoproteins. Although its tumor suppressor role in many types of cancers has been established, whether and how FBXW7 regulates in vivo esophageal tumorigenesis was previously unknown. Here, we report, using genetically modified mouse models, that Fbxw7 inhibits esophageal tumorigenesis induced by the carcinogen 4NQO (4-nitroquinoline N-oxide), but not by Pik3Ca^E545K (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), a frequently mutated gene in human esophageal squamous cell carcinoma (ESCC). Mechanistically, FBXW7 depletion causes the accumulation of SPT6 (suppressor of Ty6), a transcriptional elongation factor, which is a novel substrate of FBXW7. SPT6 acts as a transcriptional co-activator of ΔNp63, which is also a substrate of FBXW7 in ESCC cells. Both SPT6 and ΔNp63, accumulated upon FBXW7 knockdown, contribute to the proliferation of ESCC cells. In clinical human ESCC tissues, the protein levels of SPT6 and FBXW7 are inversely correlated, and high SPT6 levels with low FBXW7 levels predict poorer patient survival. Collectively, FBXW7 acts as a tumor suppressor in ESCC by promoting the degradation of both SPT6 and ΔNp63, and the SPT6-ΔNp63 axis may serve as a therapeutic target for ESCC.

Alzheimer's disease (AD) is a neurodegenerative disorder that currently lacks cures; thus, searching for new biomarkers and unraveling its underlying mechanisms are crucial for devising effective therapies. Here, we discovered that both mRNA and protein levels of CD31 (platelet endothelial cell adhesion molecule-1, PECAM1), a transmembrane glycoprotein in immunoglobulin superfamily, were significantly higher in the brains of AD individuals and different AD transgenic mice, and the elevated CD31 was related to the recognized AD pathologies. Additional studies demonstrated that systemically knockdown of CD31 in 5xFAD mice significantly improved the cognitive functions with decreased AD hallmark pathologies, including β-amyloid precipitation and tau hyperphosphorylation. Moreover, CD31 knockdown alleviated neuroinflammation, evidenced by the diminished microglial stimulation and suppressed expression of pro-inflammatory cytokines. Transcriptomic analysis indicated considerable changes in the AD-involved gene expression in 5xFAD mice, and CD31 knockdown rectified imbalanced gene expression. Mechanistically, we further revealed that CD31 knockdown suppressed the expression of STAT1 and IRF1 by reducing histone lactylation at H3K14 and H4K12, thereby modulating the transcriptional programs driving neuroinflammation and AD pathology. These findings illustrate that CD31 may act as a promising target for creating novel therapeutic strategies.

Fertility-preserving treatment (FPT) offers a critical option for young women diagnosed with atypical endometrial hyperplasia (AEH) or early-stage endometrial cancer (EC), however, the commonly used methods for evaluating complete regression (CR) are invasive. This study aimed to develop a non-invasive tool to predict treatment outcomes using radiomics and molecular profiling. We retrospectively analyzed 146 patients with AEH or early EC receiving FPT. Radiomic features extracted from MRI were used to construct a radiomics signature predictive of CR through a machine-learning approach. A radiomics-clinical nomogram integrating radiomics scores with clinical variables demonstrated excellent predictive performance, with area under the curve values of 0.963 and 0.986 in the training and validation cohorts, respectively. Patients stratified into high- and low-score groups based on radiomics scores showed significantly different CR rates, with the high-score group exhibiting a lower likelihood of CR. Single-cell RNA sequencing further confirmed immune alterations in the high-score group, including reduced CD8⁺ T-cells, and elevated levels of M2 macrophages. Bulk RNA sequencing revealed upregulation of oxidative phosphorylation and lipid metabolism pathways, suggesting a metabolically active and immunosuppressive tumor microenvironment. This radiomics-based approach holds promise for guiding individualized FPT strategies for AEH and early EC patients.

Age-associated deterioration of physiological functions occurs at heterogeneous rates across individual organs. A granular evaluation of systemic metabolic mediators of aging in a healthy human cohort (n = 225) identified prominent increases in circulating uremic toxins, a finding recapitulated in mice. We connected these systemic aging profiles to renal metabolism, specifically linking glucosylceramide (GluCer) accretion to renal functional decline at late middle-age that coincides with the temporal surge in uremic toxins. Importantly, age-associated increases in circulating GluCer, largely contributed by the kidneys, are conserved from mice to humans, and are significantly associated with enhanced risk of multiple causes of mortality in aged individuals. We further showed that GluCer accumulation, commencing in late middle-age of females, impairs mitophagy via disrupting mitochondria–lysosome untethering, and undermines mitochondrial respiratory function via purine-dependent activation of mTORC1 signaling that can be rescued by pharmacological purine depletion. The resulting age-associated renal dysfunction is female-biased, likely due to sexually dimorphic GluCer handling. Our work provides a molecular basis for the sex-specific benefits of mTOR inhibition on lifespan, and highlights clinically relevant inhibitors of purine metabolism as potential senotherapeutics to mitigate kidney-driven systemic aging.

Peroxisome proliferator‑activated receptor gamma coactivator‑1α (PGC‑1α), a key metabolic regulator, is implicated in astrocyte function, but its specific role during fear memory retrieval and in posttraumatic stress disorder (PTSD) pathogenesis remains unclear. Here, using the single-prolonged stress mice model, we demonstrated a significant downregulation of PGC‑1α specifically within hippocampal astrocytes, concomitant with reduced astrocyte density, attenuated intracellular Ca²⁺ signaling, and impaired activity‑dependent ATP release. Targeted knockdown of hippocampal astrocytic PGC‑1α in vivo was sufficient to potentiate fear memory retrieval. This behavioral enhancement was associated with a loss of complex astrocyte morphology, further suppression of ATP release, aberrant hippocampal neuronal activity, and a marked decrease in connexin 43 (CX43) expression. Notably, pharmacological inhibition of CX43‑based gap junctions mimicked this pro‑fear phenotype in control animals. Conversely, interventions either via chemogenetic activation of astrocytes or administration of PGC‑1α agonists effectively normalized fear memory responses and rescued CX43 levels in PTSD mice. Crucially, the therapeutic benefit of chemogenetic astrocyte activation was abolished when PGC‑1α was concomitantly knocked down. Collectively, our results demonstrate that PGC-1α deficiency in hippocampal astrocytes underlies enhanced fear memory retrieval in PTSD model mice, highlighting the potential of astrocyte‑targeted strategies for preventing and treating PTSD.

Lucitanib is a novel multi-target inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–3, and platelet-derived growth factor receptor α/β. This open-label, multicenter, single-arm Phase II study evaluated lucitanib plus the anti-programmed cell death 1 (PD-1) antibody toripalimab in patients with advanced solid tumors refractory to standard therapies. Patients received lucitanib (10 mg) once daily plus toripalimab (240 mg) every 3 weeks until progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) and secondary endpoints included disease control rate, duration of response, progression-free survival (PFS), overall survival, and safety. Among 131 patients across four cohorts (PD-1–treated recurrent/metastatic nasopharyngeal carcinoma [NPC], PD-1–naïve NPC, recurrent/metastatic endometrial cancer [EC], and other tumors), ORR was 34.1%, 45.8%, 38.5%, and 13.5%, respectively. Median PFS was 4.2 months (95% confidence interval [CI], 4.1–5.6), 6.5 months (95% CI, 4.0–not estimable [NE]), 5.6 months (95% CI, 2.78–11.21), and 9.7 months (95% CI, 5.4–NE). The most common Grade ≥ 3 treatment-related adverse events were hypertension (37.4%), proteinuria (10.7%), and thrombocytopenia (10.7%). Lucitanib plus toripalimab showed encouraging antitumor activity with manageable safety in heavily pretreated advanced solid tumors, supporting further randomized evaluation, particularly in NPC and EC.

Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2400087935

Tumor-derived extracellular vesicles (EVs) are a class of natural nanocarriers with phospholipid bilayers that show great promise as personalized cancer vaccine platforms due to their ability to carry tumor-specific antigens. However, their immunotherapeutic potential is hindered by limited tissue-specific targeting. In this study, we engineered tumor cell-derived EVs using an immunomodulatory peptide, DP7-C, to generate DP7-C engineered EVs (DP-EVs). These DP-EVs exhibited significantly enhanced accumulation in both lymph nodes and tumor tissues. Additionally, they demonstrated improved cellular uptake and facilitated more efficient endosomal escape. To further enhance the therapeutic efficacy, programmed cell death 1 ligand 1 targeting small interfering RNA (siPD-L1) was loaded into the DP-EVs, resulting in DP-EVs/siPD-L1. This formulation enabled concurrent suppression of PD-L1 expression in both dendritic cells (DCs) and tumor cells. In vivo experiments showed that DP-EVs/siPD-L1 significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. The observed antitumor effect was attributed to the immune activation in the lymph nodes and the remodeling of the immunosuppressive tumor microenvironment (TME). Collectively, our findings demonstrate that DP-EVs/siPD-L1 functions as an effective therapeutic vaccine, which synergistically activates antitumor immunity and reverses immunosuppression through targeted PD-L1 blockade. This engineered EV platform represents a promising and translatable strategy for cancer immunotherapy.

The Warburg effect states that cancer cells preferentially undergo aerobic glycolysis, producing lactate as a key metabolic byproduct. Lactate acidifies the tumor microenvironment (TME) and serves as a signaling molecule and substrate for lysine lactylation (Kla), a novel posttranslational modification (PTM) discovered in 2019 that links glycolytic metabolism to epigenetic and proteomic reprogramming. The reversible modification of histones and nonhistone proteins orchestrates oncogenic adaptation and drives tumor progression. However, gaps persist in our understanding of the multifactorial regulation of lactylation and its translational potential in overcoming tumor heterogeneity and resistance. This review highlights the emerging roles of lactylation in cancer therapies, including the enhancement of DNA repair mechanisms during chemotherapy, stabilization of key signaling effectors upon targeted therapy, and promotion of an immunosuppressive TME in immunotherapy. We further examined regulatory factors associated with lactylation, from competitive PTMs and genetic mutations to microbial influences and environmental signals. Additionally, we discuss the therapeutic potential of targeting lactylation via indirect modulators currently under investigation and the visualization of lactate and lactylation modifications. By synthesizing these insights, this review highlights lactylation as a reversible metabolic-epigenetic axis for precision oncology, enabling predictive biomarkers, combination strategies, and novel interventions to address the dynamic challenges of cancer.