Autoimmune diseases (ADs) arise from the breakdown of immune tolerance, yet their clinical course, organ involvement, and treatment responses vary markedly across systemic and organ-specific autoimmune disorders. This diversity cannot be explained by a single pathogenic mechanism or by conventional serological categories alone. Here, we synthesize evidence that autoimmunity is shaped by interacting molecular and cellular regulatory layers, including immunometabolic rewiring, epigenetic remodeling, posttranscriptional regulation, and functional reprogramming of immune and tissue-resident cells. These processes influence pathogenic T-cell and B-cell differentiation, myeloid activation, stromal and epithelial dysfunction, tissue-specific inflammation, and intercellular communication. We further discuss how multidimensional readouts, including metabolites, methylation and chromatin signatures, RNA-based markers, and reprogrammed immune-cell phenotypes, may support diagnosis, disease-activity assessment, prognosis, and therapeutic stratification. From a therapeutic perspective, this framework supports a shift from broad immunosuppression toward mechanism-matched interventions targeting metabolic vulnerabilities, epigenetic regulators, RNA-control pathways, and pathogenic cellular states, including emerging cell-based approaches. We propose that ADs can be viewed as dynamic network disorders in which molecular mechanisms, biomarkers, and therapeutic opportunities are closely connected. Integrating longitudinal multiomics, single-cell and spatial profiling, and standardized biomarker validation may help translate autoimmune heterogeneity into actionable precision-medicine strategies for more individualized care.
Neoadjuvant immunochemotherapy has transformed treatment paradigms in non-small cell lung cancer, yet its applicability in limited-disease small cell lung cancer (LD-SCLC) remains unknown. Here, we report findings from LungMate-006, the first prospective Phase II trial evaluating PD-1 blockade with tislelizumab combined with platinum-etoposide in LD-SCLC. Among 15 enrolled patients, the regimen achieved an objective response rate of 66.7% and enabled curative-intent surgery in 60% of patients, all with R0 resection. Major pathological response and pathological complete response occurred in 44.4% and 33.3% of surgical cases, respectively. Median event-free and overall survival reached 21.7 and 32.7 months. Metabolic response by PET-CT more accurately predicted pathological remission than radiographic shrinkage alone. Bulk RNA sequencing revealed a treatment-induced transition from a metabolically active baseline state toward an extracellular matrix-remodeled, CAF- and macrophage-enriched microenvironment, alongside upregulation of genes associated with tumor stemness and immune evasion. These transcriptomic changes suggest stromal-myeloid-mediated adaptive resistance in non-MPR tumors and highlight potential avenues for refining perioperative immunochemotherapy strategies in SCLC.
Cardiovascular diseases (CVD) remain a leading cause of death globally, yet assessing the combined impact of multiple metabolic disorders on CVD risk is challenging due to a lack of comprehensive tools. We aimed to develop and validate a novel CVD screening model based on metabolic clustering networks. Using data from 4066 adults enrolled in the STONE study (China) through stratified sampling, we constructed a holistic network map of metabolic health, incorporating obesity, dyslipidemia, glucose disorders, and hepatic, renal, thyroid, and bone conditions. Through network analysis, 12 central and clinically accessible indicators-including abdominal obesity, fatty liver, LDL-C, HbA1c, eGFR, TSH, and bone density-were selected to establish the CardioMet12 scoring system, with an AUC of 0.771 (95% CI: 0.733-0.808), sensitivity of 0.756, and specificity of 0.732. A score above 56 corresponded to an observed CVD prevalence exceeding 50% in the STONE cohort. External validation in an independent US population-based epidemiological sample demonstrated satisfactory performance. Higher scores were significantly associated with metabolic syndrome diagnosis and advanced cardiovascular-kidney-metabolic staging in both cohorts. In conclusion, CardioMet12 is a robust metric that captures the complex interplay among multiple metabolic disorders, offering a comprehensive and proactive tool for enhanced CVD screening and risk evaluation.
Exercise is a low-cost lifestyle intervention that can prevent and alleviate various diseases. It is a potent physiological stimulus that activates conserved molecular signaling pathways. Through the coordinated integration of multiple molecules, pathways, and systems, it leads to systemic health benefits. However, most studies focus on individual systems or molecular mechanisms, lacking systematic integration of the cross-system regulation induced by exercise. We summarize the molecular mechanisms of exercise in the musculoskeletal, cardiovascular, nervous systems, among others. Exercise induces the release of exerkines (e.g., irisin, interleukin-6, and brain-derived neurotrophic factor) and extracellular vesicles, which activate key signaling pathways to enhance mitochondrial function, metabolism and physiological adaptation, while suppressing inflammation and oxidative stress, thereby alleviating diseases and delaying aging through cross-system coordination. We further explore exercise-induced adaptive regulation in extreme environments, including microgravity, hyperbaria, and hypoxia, offering a multifaceted perspective on organismal health regulation. Finally, we outline the prospects and challenges of multiomics, artificial intelligence-driven precision medicine, personalized exercise prescriptions, and exercise mimetics. Overall, this review provides a more integrated perspective on the molecular basis of exercise and offers directions for future mechanistic and translational studies.
The heart and brain maintain systemic homeostasis through continuous bidirectional communication mediated by neural regulation, biochemical signaling, and mechanical transduction. Disruption of this communication is increasingly recognized as a contributor to cardiovascular, neurological, cognitive, and psychological disorders. Growing evidence indicates that autonomic imbalance, neuroimmune activation, hemodynamic disturbances, inflammation, altered interoception, and brain network remodeling can mediate cross-organ injury between the heart and brain. These mechanisms underlie a spectrum of heart-brain comorbidities, but their shared pathways, disease-specific manifestations, and integrated management strategies remain insufficiently understood. In this review, we summarize the physiological basis of heart-brain interactions, focusing on neural, biochemical, and mechanical pathways. We then discuss six representative disorders: Takotsubo syndrome, epileptic heart, stroke-heart syndrome, heart failure, cardiac dementia, and psychocardiology. For each condition, we highlight key epidemiological features, pathophysiological mechanisms, and integrated heart-brain management strategies. We also review clinical trials targeting heart-brain interactions, including autonomic modulation, biomarker monitoring, neuroimaging assessment, exercise therapy, psychological intervention, and pharmacological therapy. By integrating basic mechanisms, clinical phenotypes, and translational advances, this review provides a systematic framework for understanding heart-brain comorbidities and advancing precision heart-brain medicine.
Solitary distant metastasis (SDM) is a distinct oligometastatic subtype associated with a relatively favorable prognosis. This multicenter retrospective study including 139 non-small cell lung cancer (NSCLC) patients with SDM (2019-2024) was conducted to investigate prognostic factors for multiple metastases and identify the critical time window for local treatment. Statistical analyses included Cox regression, Kaplan-Meier survival analysis, and restricted mean survival time (RMST). Results showed that driver gene status, tumor staging, systemic therapy, and local treatment were significantly associated with progression-free survival (PFS). Notably, only early local treatment significantly delayed the onset of multiple metastases (hazard ratio [HR] = 0.55, 95% confidence interval [CI]: 0.30-0.99, p = 0.05), prolonging the median time to multiple metastases by nearly 14 months (36.4 vs. 22.6 months). Kaplan-Meier and RMST analyses revealed no distinct plateau phase, indicating the absence of an absolute temporal cutoff between "true oligo-metastasis" and "transitional metastasis," which suggests that SDM in advanced NSCLC is an inherently indolent disease state. Using the maximum selected rank statistics method, an optimal cutoff of 138 days was identified to distinguish early from delayed local treatment, which requires further prospective validation.
As a critical hub in the thalamo-cortical circuit, the human thalamus engages in a spectrum of fundamental and advanced brain functions through widely distributed circuits. Clinically, dysfunction of thalamo-cortical circuits is shown to be profoundly implicated in a wide range of neurological and psychiatric diseases. Nevertheless, the neuroanatomical substrates governing these functions of the thalamus have rarely been directly mapped in humans. Here, we overviewed the acute responses of direct electrical stimulation (DES) delivered to the distributed thalamus sites in 52 epilepsy patients admitted for presurgical stereoelectroencephalography. Specifically, DES of the thalamus evoked a broad spectrum of in-situ responses spanning fundamental functions such as sensory and motor processing, extending to complex neural operations encompassing neurovegetative regulation, cognitive processing, emotional modulation, and multimodal responsiveness. Moreover, through the integration of DES with functional human connectome (n = 1000), we found an intra-thalamic intrinsic functional network associated with each specific clinical response. Our data provide direct substantiation for the complex functional architecture of the human thalamus, advancing current understanding of its role and potentially culminating in targeted therapeutic strategies tailored to ameliorate symptom-specific neural circuit disorders.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by hyperinflammation. Primary HLH (primary HLH), resulting from genetic mutations, is a subtype of HLH. The mutation spectrum of primary HLH-associated genes has not been well determined in China. This study aimed to explore the mutation spectrum of 12 primary HLH-associated genes in a multicenter database. Medical records and gene sequencing data of 1224 HLH patients were retrieved from January 2014 to September 2024, and gene mutations were analyzed. Genetic variants were observed in 350 (28.59%) patients. Among them, 108 patients had a definitive genetic diagnosis, 227 patients carried single heterozygous variants, and 15 patients carried digenic/polygenic heterozygous variants. A total of 275 different variants were identified, and missense variants were most common. Variants in UNC13D were most common, followed by LYST and PRF1, while variants in MAGT1, ITK, and CD27 were rare. For UNC13D, LYST, and PRF1, variants c.2588G>A (p.Gly863Asp), c.368A>G (p.His123Arg), and c.1349C>T (p.Thr450Met) were most common, respectively. We described the mutation spectrum of primary HLH-associated genes in a largest Chinese cohort and found some mutation specificity for Chinese HLH patients. Our data might help design sequencing panels, interpret sequencing results, and understand genetic background of Chinese HLH patients.
Locally advanced head and neck carcinoma remains associated with high morbidity and long-term survival below 50%. Treatment commonly relies on cisplatin-based chemoradiotherapy, which is effective but frequently associated with significant acute and chronic systemic toxicities. Therefore, safer and more effective therapeutic strategies are urgently needed. FLASH radiotherapy (RT) has emerged as a promising irradiation modality because of its potential to reduce damage to healthy tissues while preserving antitumor efficacy. Here, we investigated the anticancer activity of the Topoisomerase (Topo)-II inhibitor ARN-24139, alone and combined with FLASHRT, in human papillomavirus-negative SCC-25 head and neck carcinoma biomodels. Antitumor activity was assessed in 2D cell cultures using viability, apoptosis, clonogenic, wound-healing, and γH2AX assays, as well as in SCC-25 3D spheroids and in chorioallantoic membrane (CAM) tumor models. ARN-24139 induced dose-dependent cytotoxicity in SCC-25 cells, with IC50 values of 7.3 ± 0.8 µM at 48 h and 7.2 ± 0.5 µM at 72 h, while showing limited toxicity in healthy HBEpC cells. Sequential low-dose FLASH-RT followed by ARN-24139 enhanced antitumor activity, reducing cell viability at 4 Gy after 8 days and decreasing tumor growth and Ki67 expression in CAM models. These proof-of-concept findings support further investigation in more clinically representative and mechanistically informative HNSCC models.
Cancer nanomedicine offers a versatile platform for improving therapeutic index, but its clinical translation remains limited by unpredictable in vivo behavior, heterogeneous biological contexts, and inefficient design paradigms. Artificial intelligence (AI) is emerging as an integrative framework that links data-driven modeling with nanomedicine design, biological transport, and clinical decision-making. In this review, we discuss AI-guided strategies for material design, targeting, payload optimization, and in vivo delivery, with particular attention to protein corona-mediated biological identity, microenvironment-responsive activation, and biodistribution modeling. We further examine the translational requirements for AI-enabled nanomedicine, including data standardization, preclinical learning workflows, clinical stratification and risk-based governance. Finally, we outline future directions centered on transferable learning architectures, dynamic multiscale modeling and patient-aware therapeutic strategies. Together, these advances suggest that AI can move cancer nanomedicine beyond empirical formulation toward a more predictive, biologically informed, and clinically responsive discipline.
Ursodeoxycholic acid (UDCA) decreases angiotensin-converting enzyme 2 (ACE2) activities by inhibiting farnesoid X receptor (FXR). To investigate the role of UDCA in decreasing SARS-CoV-2 infection and affecting COVID-19 cytokine levels, COVID-19 patients (n = 142, male = 72, female = 70) were divided into UDCA-free (n = 53) and UDCA (n = 89) groups and treated with nirmatasvir/ritonavir or molnupiravir for 5 days. Patients in the UDCA group were additionally administered UDCA for 10 days. On Day 0 (before treatment), 3, 6, and 9 (after anti-viral drug and/or UDCA treatment), levels of ACE2 in serum and plasma or ACE2 mRNA in blood cells in the UDCA groups were significantly lower than those in the UDCA-free group. In Calu-3 cells, UDCA reduced ACE2 protein and mRNA, and blocked the COVID-19 spike (XBB.1.5) pseudovirus infection. Serum cytokines have been detected in COVID-19 patients with or without taking UDCA. Among the 46 cytokines analyzed, luminex profiling revealed that 21 proinflammatory cytokines, including CTACK, bFGF, G-CSF, GM-CSF, GRO-α, IL-1β, IL-1Ra, IL-2, IL-2Rα, IL-6, IL-10, IL-16, IP-10, MCP-1, MCP-3, MIG, TNF-α, TRAIL, VEGF, IL-9, and IL-18, were significantly lower with UDCA treatment (p < 0.01), whereas only eotaxin levels increased (p < 0.05). Therefore, UDCA reduces ACE2 activity, improves clinical outcomes, and suppresses cytokine storm syndrome (CSS) in COVID-19 patients.
Migraine is a common, disabling brain disorder that affects about 1 billion people worldwide and disproportionately burdens women and working-age adults. Once viewed mainly as a vascular headache, migraine is now understood as a heterogeneous neurobiological syndrome arising from interactions among genetic susceptibility, hormonal influences, environmental exposures, and cortical, brainstem, trigeminovascular, and neuroinflammatory networks. Although calcitonin gene-related peptide (CGRP)-pathway therapies, gepants, and neuromodulation have transformed care, major gaps remain in disease stratification, prevention of chronification and management of special populations. Here, we review recent evidence on global and regional epidemiology, sex-specific and environmental risk factors, and the transition from episodic to chronic migraine. We then examine current mechanistic models, focusing on cortical spreading depolarization, trigeminovascular signaling, CGRP biology, neurogenic inflammation, glial activation, and brain network dysfunction. We also assess acute and preventive treatment strategies, including ditans, gepants, monoclonal antibodies, and onabotulinumtoxinA, and discuss persistent challenges in pediatric, geriatric, and pregnancy-associated migraine care. By integrating population, mechanistic and therapeutic perspectives, this review reframes migraine as a stratified brain network disorder rather than a uniform vascular pain syndrome. This synthesis highlights priorities for biomarker development, precision medicine, and more equitable implementation of effective migraine care.
The immune response is a highly dynamic and precisely controlled process, and relies on an intricate network of protein interactions to maintain its homeostasis. Protein posttranslational modifications (PTMs), by covalent addition of chemical groups or peptide chains, or by proteolytic cleavage, directly alter the structure, activity, electrical charge, thermal stability, and function of immune-related proteins. Here, we enumerate the main PTMs in the immune system and highlight their global regulatory roles across innate immunity, T-cell-mediated cellular immunity, and B-cell-mediated humoral immunity, including phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, glycosylation, and other new types. We focus on how these modifications regulate antigen presentation and recognition, immune signal transduction, antibody production and class switching, immune contraction, immune memory establishment, as well as immune tolerance and homeostasis. Critically, dysregulation of host protein PTMs disrupts immune homeostasis, which in turn induces numerous immune-related diseases, including cancer, autoimmune diseases, and infectious diseases. By integrating mechanistic insights with emerging therapeutic strategies, this review provides a comprehensive PTM network that elucidates the molecular basis of immune-related diseases and highlights promising immunotherapeutic strategies targeting these modifications.
Metabolic reprogramming is a central feature of many human diseases, and therapies that target altered metabolic dependencies are moving from concept to clinical testing. Amino acid homeostasis links essential and nonessential amino acid supply with branched-chain amino acid (BCAA) catabolism, one-carbon metabolism, mechanistic target of rapamycin complex 1 (mTORC1)/general control nonderepressible 2 (GCN2) nutrient sensing, glutathione-dependent redox control, epigenetic regulation, and the gut microbiota-amino acid axis. When this network is disturbed, amino acid flux can contribute to disease initiation and progression rather than simply mirroring established pathology. This review synthesizes how amino acid metabolism supports the nervous, cardiovascular, digestive, metabolic-endocrine, immune, skeletal, urinary and reproductive systems, as well as malignant and inherited metabolic disorders. We also examine how pathway-level disturbances converge on excitotoxicity, endothelial dysfunction, insulin resistance, inflammation, fibrosis, immune escape, toxic metabolite accumulation, and impaired fertility. Rather than catalog isolated findings, we emphasize unifying principles and unresolved controversies, including the context-dependent effects of BCAA signaling, the causal versus biomarker status of circulating amino acid signatures, host-gut microbiome crosstalk, and the therapeutic window of dietary, enzymatic, transporter-targeted, and microbiota-based interventions. Finally, we assess clinical translation, drawing lessons from late-stage trial failures and emerging strategies with realistic potential for precision metabolic therapy.
Ischemia/reperfusion (I/R)-induced acute lung injury (ALI) is a severe clinical syndrome characterized by alveolar epithelial damage, oxidative stress, and acute respiratory failure, but the epitranscriptomic mechanisms linking N6-methyladenosine (m6A) modification to ferroptosis remain unclear. Clinical profiling of end-stage acute respiratory distress syndrome (ARDS) patients showed hyperinflammation, reflected by elevated C-reactive protein and procalcitonin, coagulopathy with abnormal D-dimer levels, and severely impaired gas exchange. Reanalysis of a public murine single-cell RNA sequencing dataset revealed enrichment of RNA methylation-, ubiquitination-, and ferroptosis-related programs in injured lung epithelial cells. Integrated methylated RNA immunoprecipitation sequencing and RNA sequencing of I/R-injured mouse lungs further identified methyltransferase-like 14 (METTL14) and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) as candidate m6A regulators. Human ARDS tissues and mouse I/R lungs confirmed increased METTL14, ubiquitin-specific peptidase 30 (USP30), and nuclear receptor coactivator 4 (NCOA4) expression. Mechanistically, METTL14-mediated m6A modification enhanced USP30 expression through YTHDF1 recognition, whereas USP30 stabilized NCOA4 by reducing K48-linked polyubiquitination. Stabilized NCOA4 promoted ferritinophagy, Fe2 + accumulation, lipid peroxidation, and epithelial ferroptosis. These findings identify a METTL14/YTHDF1-USP30-NCOA4 axis as a potential therapeutic target for ferroptosis-driven I/R-induced ALI.
This study developed an integrated strategy combining surface plasmon resonance (SPR) for real-time biomolecular interaction analysis, ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) for compound profiling, and Global Natural Products Social Molecular Networking (GNPS)-based molecular networking for structural annotation in complex herbal systems. Using this platform, we identified hypermonol J (HPJ), a polycyclic polyprenylated acylphloroglucinol (PPAP), as a high-affinity small-molecule binder of tumor necrosis factor (TNF) (K D = 25.9 pM). SPR and orthogonal isothermal titration calorimetry (ITC) supported direct TNF binding, whereas mechanistic assays suggested that HPJ may preferentially stabilize TNF dimers, thereby impairing trimer assembly and downstream TNF receptor 1 (TNFR1)/nuclear factor kappa B (NF-κB) signaling. In a preclinical psoriasis model, topical 1% HPJ alleviated imiquimod (IMQ)-induced epidermal hyperplasia and suppressed IL-17/IL-23 pathways. In an acute lung injury (ALI) model, 10 mg/kg HPJ reduced neutrophil infiltration, lowered serum inflammatory cytokine levels, and restored pulmonary tight junction integrity. Biosafety assessments supported the preliminary tolerability of HPJ under the tested conditions. These findings identify HPJ as a promising small-molecule lead for further pharmacological optimization and underscore the value of SPR-guided natural product discovery for inflammatory storm intervention.
Steroid-refractory (SR) gastrointestinal (GI) acute graft-versus-host disease (aGVHD) is the major cause of early mortality after allogeneic hematopoietic stem cell transplantation. Vedolizumab could be used as the second- or third-line treatment of GI-aGVHD. Our real-world, retrospective multicenter study, in which 100 SR-GI-aGVHD patients who received vedolizumab were enrolled, confirmed its effectiveness. Note that 411 SR-GI-aGVHD patients who received the best available treatments (BATs) during the same period were enrolled as controls. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were conducted as sensitivity analyses. The overall response rates (ORRs) for SR-GI-aGVHD on day 28 and at any time point were 68.0% and 81.0%, respectively, and the 2-year probabilities of overall survival and nonrelapse mortality were 58.3% and 31.9%, respectively, after vedolizumab treatment. Multivariate analysis revealed that initiating vedolizumab treatment within 7 days after SR-aGVHD onset could help improve the ORR. In the sensitivity analysis, compared with the BATs, vedolizumab improved the ORR and complete response rate, particularly in the stage 3-4 SR-GI-aGVHD subgroup, and it reduced the infection rate after IPTW and PSM adjustment. These findings confirmed the efficacy of vedolizumab in a real-world setting, which can help to control SR-GI-aGVHD more effectively and safely.
Ferroptosis is a novel, iron-driven form of cell death characterized by iron-dependent membrane-lipid peroxidation. Accumulating evidence has revealed that ferroptosis is heavily involved in multiple physiological and pathological conditions, resulting in remarkable progress in the treatment of multiple diseases. This review summarizes recent advances in and the fundamental features of ferroptosis and outlines the molecular mechanisms that regulate core metabolic pathways and their relevance to cellular physiology. In addition, the mechanisms and functional implications of ferroptosis in cancer, cardiovascular diseases, neurodegenerative disorders, and acute organ injury are discussed, and current diagnostic and therapeutic strategies that target ferroptosis are summarized. Finally, the review identifies persistent gaps in the mechanistic understanding, relevant biomarker development, and translational validity of ferroptosis to provide a comprehensive foundation for future research and clinical innovation in the era of precision medicine.
