Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy worldwide. Although ferroptosis has been implicated in cardiac pathogenesis, its regulatory mechanism in DCM remained poorly defined. In this study, we found that GIPC1 (GAIP/RGS19-interacting protein), a scaffolding protein, was significantly downregulated in cardiac tissues from DCM patients and doxorubicin (DOX)-induced DCM models. Integrated proteomic and lipidomic analysis revealed that cardiac-specific knockout of GIPC1 disrupted mitochondrial fatty acid metabolism, increased the abundance of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), and ultimately promoted ferroptosis in cardiomyocytes. Both in vitro and in vivo experiments demonstrated that GIPC1 deficiency exacerbated ferroptosis and cardiac dysfunction in DOX-induced cardiomyopathy, whereas GIPC1 overexpression conferred protection against ferroptosis in DOX-induced cardiomyopathy. Mechanistically, co-immunoprecipitation mass spectrometry (Co-IP/MS) and molecular docking demonstrated that GIPC1 interacted with mitochondrial 2,4-dienoyl-CoA reductase (DECR1) via its PDZ domain. Surface plasmon resonance (SPR) analysis further confirmed a high-affinity direct binding between GIPC1 and DECR1 (KD = 16.3 nM). Co-IP and immunofluorescence (IF) demonstrated that GIPC1 facilitated actin-dependent transport of DECR1 into mitochondria, thereby maintaining redox homeostasis and suppressing ferroptosis. Consistently, DECR1 overexpression rescued GIPC1 ablation-induced ferroptosis by balancing redox homeostasis. Together, these results demonstrated that GIPC1 reduced cardiomyocyte susceptibility to ferroptosis by promoting mitochondrial translocation of DECR1 and remodeling lipid homeostasis, highlighting GIPC1/DECR1 axis as a potential therapeutic strategy for DCM. A schematic model illustrating the pathogenic cascade triggered by GIPC1 deficiency during DCM. In DCM, the expression level of GIPC1 was downregulated, thereby inhibiting actin-dependent transport of DECR1 into mitochondria, which remodeled lipid homeostasis and ultimately induced cardiomyocytes ferroptosis. Created with Figdraw.com.

ETHNOPHARMACOLOGICAL RELEVANCE:Sinisan (SNS) is a classic traditional Chinese herbal formula originating from Treatise on Cold Damage Disorders, which has been traditionally used to harmonize the liver and spleen, regulate qi dynamics, and relieve abdominal pain and gastrointestinal discomfort. Clinically, SNS has long been applied for disorders characterized by liver-spleen disharmony, including functional and stress-related gastrointestinal conditions. However, its protective effects and underlying mechanisms in stress-induced gastric ulcer (SGU) remain unclear. OBJECTIVE:To evaluate the protective effects of SNS on SGU in mice and to elucidate the underlying molecular mechanisms. METHOD:Mice were pretreated with SNS at doses of 2.4, 4.8, and 9.6 g/kg by oral gavage for seven consecutive days prior to induction of stress gastric ulcer using the water-immersion restraint method. Gastric mucosal injury was evaluated by macroscopic observation and histopathological examination (H&E and PAS staining). Oxidative stress parameters, including ROS, MDA, SOD, and GSH-Px, were measured using commercial assay kits. Protein expression levels of TLR4, MyD88, and NF-κB in gastric tissues were determined by Western blot analysis, and serum inflammatory cytokines (TNF-α, IL-1β, and IL-6) were quantified by ELISA. LC-MS/MS was performed to identify absorbed constituents, followed by network pharmacology and molecular docking analysis. RESULTS:Study showed that SNS protected the gastric mucosal structure, alleviated inflammation, effectively preserved the epithelial layer, and reduced oxidative stress in gastric tissues. It inhibited the expression of TLR4, NF-κB, and MyD88 proteins in gastric tissues, thereby reducing the inflammatory response. ROS and MDA levels were decreased, whereas SOD and GSH-Px activities were increased in gastric tissues compared with the model group. Enrichment analysis suggested that SNS may exert anti-SGU effects through multiple pathways, including the Toll-like receptor signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. Potential active compounds contributing to the protective effects of SNS on the gastric mucosa were identified using LC-MS combined with bioinformatics analysis. CONCLUSION:SNS pretreatment exerts protective effects against stress-induced gastric ulcer by modulating the TLR4/NF-κB signaling pathway, thereby attenuating inflammatory responses and gastric mucosal injury.

Heart failure (HF) represents the final stage of cardiovascular disease progression, characterized by high morbidity and mortality. Pressure overload in HF activates the PI3K/AKT pathway, and prolonged activation leads to pathological cardiac hypertrophy. However, the mechanism underlying sustained PI3K/AKT activation in pressure overload-induced HF remains unclear. In this study, we demonstrate that miR-203 overexpression in transgenic mice counteracts cardiac dysfunction and pathological remodeling in HF, whereas miR-203 downregulation exacerbates HF. At the cellular level, miR-203 overexpression significantly reduces Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and injury, while miR-203 knockdown aggravates these effects. Mechanistically, miR-203 binds to the 3’ untranslated region (3’UTR) of insulin-like growth factor binding protein 5 (IGFBP5) mRNA, inhibiting IGFBP5 protein expression, thereby suppressing PI3K/AKT signaling and mitigating cardiomyocyte hypertrophy. Furthermore, we demonstrate that fibronectin-1 (FN1) is a critical functional partner for IGFBP5, as knockdown of FN1 attenuates IGFBP5-induced PI3K/AKT activation and hypertrophy. This study is the first to elucidate the role and mechanism of miR-203 in regulating pressure overload-induced HF, offering a potential genetic tool for HF therapy.

BACKGROUND:Myocardial ischemia/reperfusion (I/R) injury induces an intense inflammatory response and involves multiple cell death pathways. PANoptosis, an integrated cell death process involving pyroptosis, apoptosis and necroptosis, is a major driver of cardiomyocyte loss during I/R injury. However, the epitranscriptomic control of PANoptosis is poorly understood. METHODS:We investigated the role of ALKBH3, an mRNA N1-methyladenosine (m1A) demethylase, in the regulation of cardiomyocyte PANoptosis using hypoxia/reoxygenation models in vitro and murine I/R models in vivo. Integrated transcriptomic and m1A epitranscriptomic profiling identified downstream targets. Loss- and gain-of-function studies of ALKBH3, AIM2, ZBED6 and STAT1 (siRNA or plasmid overexpression) were coupled with assessments of cell death phenotypes, inflammasome activity and gene expression. Molecular interactions and transcriptional/translational regulation were examined using co-immunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS:Cardiomyocyte-restricted ALKBH3 overexpression mitigates I/R injury in vivo. Mechanistically, ALKBH3 acts as a key suppressor of PANoptosis by inhibiting AIM2. ALKBH3 demethylates m1A onZBED6 mRNA, enhancing ZBED6 translation and limiting cardiomyocyte PANoptosis. Although ZBED6 does not bind directly to the AIM2 promoter, it physically interacts with STAT1, a transcriptional activator of AIM2, and represses STAT1-driven AIM2 expression. ZBED6 overexpression reduces AIM2 levels and PANoptosis, whereas AIM2 knockout attenuates the exacerbation of cardiac injury and PANoptosis induced by ALKBH3 silencing. CONCLUSIONS:These findings identify the ALKBH3/ZBED6/STAT1/AIM2 signalling axis that epitranscriptomically breaks cardiomyocyte PANoptosis, highlighting a tractable therapeutic target that limits cell death and improves myocardial outcomes after I/R.

Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence, yet its precise pathogenesis remains unclear. MicroRNAs (miRNAs) have been widely implicated in tumorigenesis. Although studies suggest that miR-196b is closely associated with the progression of various malignancies, its specific biological functions and mechanisms in EC remain to be elucidated. In this study, analysis of tissue and serum samples from EC patients revealed that miR-196b is downregulated in EC, whereas GATA6 is upregulated, with a notable negative correlation between their expression levels. In Ishikawa and HEC-1 A EC cell lines, functional assays including CCK-8, colony formation, wound healing, and Transwell experiments revealed that downregulation of miR-196b significantly enhanced cell proliferation, migration, and invasion. A nude mouse xenograft model further confirmed that high miR-196b expression weakened the tumorigenic ability of EC cells. Mechanistically, dual-luciferase reporter assays identified GATA6 as a direct target of miR-196b. Downregulation of miR-196b facilitated the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) of EC cells by up-regulating GATA6. The miR-196b/GATA6 axis is involved in regulating the activity of the AKT/ERK signaling pathway. Furthermore, through a series of bioinformatics analyses, we found that miR-196b and GATA6 have potential as diagnostic and prognostic markers for EC. This study elucidates the molecular mechanism by which miR-196b suppresses EC progression by targeting GATA6. These findings provide novel insights into the pathogenesis of EC and highlight the potential of miR-196b/GATA6 as a diagnostic and prognostic biomarker.

Endometriosis, affecting approximately 10% of reproductive-aged women worldwide, is widely recognized as a chronic inflammatory disease. Inflammation-related genes (IRGs) play a crucial role in the occurrence and progression of various diseases, including endometriosis. However, identifying the key IRGs that drive endometriosis pathologyand whether they can be therapeutically targeted remains unclear. In the present study, the ectopic endometrium (EcE) and eutopic endometrium (EuE) from endometriosis patients were collected and a mouse model of endometriosis was established to investigate the expression levels of inflammatory factors. Three hub IRGs (CCL21, CFD, and ACKR1) in endometriosis were identified, which were able to accurately predict the occurrence of endometriosis. The expression of CCL21 was significantly increased in the EcE in EcE from patients with endometriosis and in endometriosis-like lesions from mice. Knockdown of CCL21 inhibited the proliferation, migration, and invasion of 12z cells and promoted apoptosis. Mechanistically, CCL21 knockdown attenuated endometriosis-associated inflammatory signaling through restraining the activation of the NF-κB signaling pathway and the downstream inflammatory factors (IL-6, IL-1β, and TNF-α). In conclusion, increased CCL21 promoted the development of endometriosis by regulating inflammatory cytokine and activating the NF-κB signaling pathway. This finding offers a novel therapeutic target for treatment.

Synovial sarcoma (SS) is a rare and aggressive soft tissue malignancy characterized by t(X;18)(p11.2;q11.2) translocation, which results in the SYT-SSX fusion gene. SS exhibits cancer stem cell-like properties that contribute to its invasiveness. Recent evidence implicates microRNA-29b (miR-29b) could regulate TGF-β pathway and its downstream gene EP300 may be involved in these traits. Bioinformatics tools (miRDB, TargetScan, and miRanda) were used to predict the interaction between miR-29b-5p and EP300, which was validated via dual-luciferase reporter assays and RNA-binding protein immunoprecipitation. The expression levels of miR-29b-5p and EP300, along with those of cancer stem cell markers, LIF-LIFR signaling, and Ki-67 proliferation indices, were analyzed in SS tissues, parental cells, and spheroid cells. Spheroids derived from SW982 and SSX1 cells cultured in serum-free suspension presented elevated levels of cancer stem cell markers and increased proliferation, migration, and invasion capacities, particularly SYT-SSX1-derived spheroids. Compared with parental cells, spheroids presented reduced miR-29b-5p expression and increased EP300 expression. The overexpression of miR-29b-5p suppressed spheroid formation; stemness marker expression; and cell proliferation, migration, and invasion, whereas its inhibition had the opposite effect. Compared with individual silencing, co-silencing of miR-29b-5p and EP300 further attenuated cancer stem cell-like traits, underscoring their regulatory interplay. In conclusion, miR-29b-5p may suppresses cancer stemness and aggressiveness in SS to some extent by targeting EP300, with a relatively more pronounced effect in SSX1 cells. Preliminarily these fundings suggest that miR-29b-5p-mediated modulation of EP300 and the TGF-β signaling pathway may provide a potential research data for synovial sarcoma studies.

Aspartate-specific cysteine protease (Caspase)-8 plays a critical role in initiating pyroptosis by mediating cleavage and activation of gasdermin-D (Gsdmd) during Yersinia infection. However, the role of Caspase-8 in pyroptosis after myocardial infarction (MI) and its underlying mechanism remains elusive. Here we show that Caspase-8 is essential for cardiomyocyte pyroptosis post MI and Caspase-8/Gsdmd signaling pathway is activated in hearts of male infarcted mice. The inhibition of Caspase-8 in male mice rescues the decline of cardiac function and cardiomyocyte pyroptosis following MI. Dnmt3a is further shown to impact DNA methylation on the CpG island of Caspase-8 promoter and regulate Caspase-8 expression. Dnmt3a overexpression protects myocardium from MI in male mice by inhibiting cardiomyocyte pyroptosis. Moreover, reduction of Dnmt3a in MI is attributed to the increased ubiquitination. Our study identifies a regulatory axis, Dnmt3a/Caspase-8/Gsdmd, which drives ischemic heart injury by promoting cardiomyocyte pyroptosis, and suggests potential therapeutic targets for heart diseases.

High-fat diet (HFD)-induced gut dysbiosis precipitates hippocampal mitochondrial oxidative stress, a pivotal driver of synaptic failure and cognitive decline. However, the molecular conduits linking intestinal microbial shifts to cerebral redox imbalance remain poorly defined, limiting therapeutic strategies. Here, we show that luteolin attenuates HFD-induced cognitive impairment in association with modulation of the gut microbiota-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) axis and improved mitochondrial redox homeostasis. Luteolin treatment ameliorated HFD-induced memory deficits and metabolic abnormalities in mice, effects that were markedly reduced after gut microbiota depletion and were transmissible via fecal microbiota transplantation. Consistent with this pathway, luteolin suppressed HFD-induced expansion of Proteobacteria (e.g., Escherichia coli), diminished intestinal lipopolysaccharide (LPS) leakage, and normalized colonic indoleamine 2,3-dioxygenase 1 (IDO1) expression. Consequently, luteolin reduced peripheral and hippocampal Kyn accumulation, thereby restricting AhR nuclear translocation and preventing the aberrant transcription of AhR-target genes implicated in mitochondrial respiratory chain disruption. Functionally, luteolin restored hippocampal mitochondrial bioenergetics, attenuated pathological reactive oxygen species (ROS) overload, and preserved synaptic long-term potentiation (LTP). The protective efficacy of luteolin against mitochondrial oxidative insult and cognitive decline was phenocopied by AhR inhibition and abrogated by exogenous Kyn supplementation. Collectively, our findings identify the gut Proteobacteria-Kyn-AhR signaling axis as an important contributor to hippocampal mitochondrial oxidative stress in HFD-challenged brains. Luteolin emerges as a promising microbiota-targeted antioxidant intervention that safeguards cognitive function by rectifying this gut-brain redox relay.

Objectives Cardiac Arrest (CA) is a serious event that threatens life. However, the early proteomic characteristics of CA remain poorly understood. We sought to systematically identify CA-related proteins in a prospective cohort and construct a predictive model. Methods The plasma proteomic data were obtained from the UK Biobank cohort and included 2,923 plasma proteins and 351 CA cases. The Cox proportional hazards regression model was used to investigate the association between proteins and CA. Locally estimated scatterplot smoothing was used to model the relationship between plasma protein levels and CA progression. Plasma proteins and clinical risk factors significantly associated with CA were used to build Cox proportional hazards regression models to predict the risk of CA events. Model discrimination was quantified by the area under the curve (AUC) of receiver operating characteristic (ROC). Results We identified 38 significant CA-related proteins over a 14-year follow-up period. The top notable proteins included GDF15, TNFRSF10B and IGFBP7, which exhibited abnormal levels 14 years prior to diagnosis and demonstrated a consistent upward trend. These CA-related proteins were primarily involved in biological functions such as collagen containing extracellular matrix, humoral immune response, and cytokine activity. Among them, 26 proteins exhibited abnormal fluctuations throughout the entire follow-up period, demonstrating strong predictive performance with an AUC of 0.822 in the test set when combined with demographic indicators to construct a predictive model. Conclusions Our study identified plasma protein fluctuation patterns 14 years before CA, providing insights into its pathogenesis and offering opportunities for early warning.

Background High body mass index (BMI) presents a serious and ongoing global health challenge. However, the difficulty of high BMI intervention has not yet been systematically evaluated. Methods We developed a Generative Artificial Intelligence Meta-Evaluation (GAME) framework, which integrated 18 indicators from 4 dimensions, including "Macro-System Level", "Socio-Cultural Level", "Community-Family Level", and "Individual Level" to evaluate the difficulty of high BMI intervention across 226 locations. The GAME framework applies 8 leading AI models to generate intervention difficulty scores (IDS) of each indicator on a scale from 1 to 5, with higher scores indicating greater difficulty. Meta-analysis was conducted to derive combined scores, evaluate the heterogeneity and sensitivity. Final intervention difficulty scores were calculated as the weighted sum of all 18 indicators. Additionally, SHapley Additive exPlanation (SHAP) values were used to evaluate the importance of each indicator in determining the intervention difficulty. Results The global difficulty of high BMI intervention shows significant imbalance. Norway (IDS = 1.48) exhibited the easiest intervention, while Yemen (IDS = 4.56) faced the greatest challenge. Regions such as Western Europe, Australasia, and High-income Asia Pacific showed lower intervention difficulty, reflecting there are mature public health frameworks, supportive social-cultural environments for healthy lifestyles, and high levels of health awareness. On the contrary, countries in North Africa and Middle East, South Asia, Oceania, and Sub-Saharan Africa faced higher intervention challenges, suggesting the need for long-term, collaborative efforts from multiple sectors. Among the 18 indicators, "Cognition and Awareness" has the most significant impact on intervention difficulty, with the SHAP value of 31.03, followed by "Family life and cognitive patterns" (18.08) and "Health Care System" (11.7). Furthermore, the IDS for high BMI was significantly correlated with Socio-Demographic Index (SDI). Higher SDI values were associated with easier interventions. Finally, the independent external empirical verification demonstrated high consistency between intervention difficulty and increase in annual prevalence of obesity, population mean BMI, and national policies. It supported the GAME framework to characterize global heterogeneity in high BMI intervention challenge. Global results were freely available at http://www.deepburden.com/high-bmi. Conclusion The difficulty of high BMI intervention varies widely across countries and regions, highlighting the need for comprehensive strategies and governance to address the growing health issue effectively. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Natural Science Foundation of China (Grant Nos. 31970651, 92286018); the Excellent Youth Support plan of Education Department of Heilongjiang Province (Grant No. YQJH2023036); Marshal Initiative Funding (Grant No. HMUMIF-22010); XingLian Outstanding Talent Support Program 2024; and the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (Grant No. LBY24H170001). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Galactosemia, a genetic disorder caused by mutations in the human GALT gene, often leads to multi-organ damage, with liver injury being particularly prominent. To elucidate the molecular mechanisms of Galt in liver injury, this study employed the CRISPR/Cas9 system to construct a Galt (c.847 + 1G > T) gene-edited mouse (GAL mouse) model. Quantitative Real-time PCR and Western blotting revealed a significant reduction of Galt gene in GAL mice. Elevated liver index, serum ALT and AST levels, and H&E staining results indicated significant hepatocyte edema in GAL mice, suggesting a pronounced liver injury phenotype. Single-cell transcriptomics further unveiled significant changes in hepatocyte subtype proportions, with downregulation of metabolism-related genes and upregulation of immune-related genes. Cell communication analysis demonstrated that the communication of HGF and VEGF signaling pathways was significantly enhanced following Galt gene editing. The enhancement of HGF and VEGF signaling pathways may lead to hepatocyte edema, thereby causing liver injury. The GAL mouse model constructed in this study not only revealed the crucial roles of the Galt gene in liver metabolism, immune regulation, and cell communication, but also provided new insights into the pathogenesis of galactosemia and potential therapeutic targets.

OBJECTIVES:Coronary atherosclerosis (CA) can remain subclinical for decades before clinical onset, while the complex pathophysiological mechanisms underlying its progression remain poorly understood. Proteomics offers a novel perspective for elucidating its pathogenic mechanisms and improving risk prediction. METHODS:The plasma proteomic data were from 29,020 UK Biobank participants comprising 2,907 Olink-measured proteins. 1,000 iterations of resampling-based univariable Cox regression were performed to identify robust CA-associated proteins. Locally estimated scatterplot smoothing was used to model the temporal trajectories of CA-associated proteins. Cox proportional hazards models integrating CA-associated proteins with traditional risk factors were constructed to predict incident CA, with model performance evaluated using the area under the curve (AUC) of receiver operating characteristic (ROC). RESULTS:During the 15-year follow-up, 65 proteins were found to be significantly associated with CA risk across the long-term, short-term, and overall follow-up periods. These CA-associated proteins were predominantly involved in collagen-containing extracellular matrix, endoplasmic reticulum lumen, and defense response to bacterium. By integrating multi-stage significance rankings using the robust rank aggregation method, we identified 5 key candidate proteins. Among these proteins, MMP12 remained persistently elevated 15 years before CA diagnosis, whereas GDF15, WFDC2, EDA2R and CST3 exhibited progressive abnormalities approximately 8 to 13 years prior to diagnosis. The model constructed using only the 5 key candidate proteins combined with traditional risk factors achieved high accuracy for 10-year (AUC = 0.749) and 5-year (AUC = 0.722) CA risk prediction. CONCLUSIONS:This study provides a temporal proteomic landscape of CA progression and highlights a compact panel of five plasma proteins that effectively predict CA risk. These findings not only advance understanding of the molecular mechanisms driving CA but also offer translational potential for early detection and precision prevention in clinical practice.

Hyperspectral image (HSI) classification requires reliable pixel-relation modeling under spectral variability, mixed pixels, and heterogeneous boundaries. Existing graph-based HSI classifiers usually construct graph topology from spatial proximity, superpixel connectivity, or learned feature affinity. However, the spectral physical prior carried by contiguous bands has limited influence on topology estimation and message propagation. This paper presents DAPGNet, a dynamic adaptive physics-guided graph diffusion network that injects a structure-constrained physical prior into relation-level graph learning. DAPGNet first encodes contiguous spectral responses into node-wise multiscale physical-prior representations. A two-stage graph constructor then combines spectral-spatial affinity, physical-prior consistency, and spatial distance to form a physical-prior-aware sparse topology. During graph diffusion, learned edge weights are transformed into additive attention biases, while a physical gate performs node-wise and feature-wise interpolation between graph-aggregated features and projected physical-prior features. Cross-scale fusion integrates node states from different diffusion depths, and the network is optimized with main classification, auxiliary supervision, and second-order spectral smoothness regularization. Experiments on Indian Pines, WHU-Hi-LongKou, Houston2013, and Houston2018 show that DAPGNet achieves the best OA, AA, and Kappa among representative CNN-, Transformer-, Mamba-, and graph-based baselines. It improves AA over the strongest competing method by 3.64 to 7.31 percentage points across the four datasets. Ablation and sensitivity analyses further support the complementary effects of physical-prior extraction, prior-aware topology construction, physics-gated propagation, and spectral smoothness regularization.

BACKGROUND:Type 1 diabetes (T1D) is a common disease. Although genome-wide association studies (GWASs) have identified hundreds of associated single nucleotide polymorphisms (SNPs), very few T1D GWAS have simultaneously addressed both Asian and European populations. METHODS:Here, we conducted a large-scale trans-ancestry meta-analysis including 680,539 European individuals (12,525 T1D cases and 668,014 controls) and 133,251 Asian individuals (1,219 T1D cases and 132,032 controls) to identify genetic associations with T1D. Subsequently, fine-mapping and Summary-data-based Mendelian randomization (SMR) analyses were performed to further refine T1D-related genetic signals. RESULTS:We identified 27 T1D-associated loci, including 8 potentially novel loci (near CDKAL1, NRSN1, FAM65B, LRRC16A, TULP1, SLC17A3, LRIG2, C6orf1). Fine-mapping was performed and helped pinpoint 7 putative causal variants (posterior probability, PP > 0.95) with T1D. Among them, rs9366622 (PP = 0.976) and rs1165190 (PP = 0.996) are located near LRRC16A and SLC17A3, respectively. These two variants are the lead SNPs of identified novel loci. SMR analysis identified a putative risk gene (U91328.19) at the novel locus SLC17A3-rs1165190, whose expression level is causally associated with T1D. CONCLUSIONS:These findings suggest that, for T1D, increasing ancestral diversity in genetic studies helps identify core genes and provides new insights into pathogenesis.

Chaperone-mediated autophagy (CMA) is a critical biological process responsible for degrading proteins in lysosomes. Our previous studies demonstrated that impaired CMA in macrophages accelerated atherosclerosis under normoxic conditions. Hypoxia is an independent risk factor for atherosclerosis, and the role of CMA in atherosclerosis under hypoxic conditions is not clear. In this study, we generated myeloid-specific LAMP2A-knockout mice and LAMP2A-deficient THP-1 macrophage cells to investigate the role of CMA in hypoxia-induced atherosclerosis. We found that the expression of LAMP2A, the rate-limiting component of CMA, was increased in peripheral blood mononuclear cells (PBMCs) from patients with obstructive sleep apnoea syndrome (OSAS) and in atherosclerotic plaques of ApoE-/- mice exposed to hypoxic conditions. Furthermore, knockout of LAMP2A in macrophages promoted the development of atherosclerosis in vivo under hypoxic conditions, along with an obvious impairment of mitophagy in atherosclerotic plaques and in LAMP2A-deficient THP-1 macrophages. Mechanistically, LAMP2A deficiency impaired mitophagy by inhibiting the expression of NIX/BCL2-interacting protein 3 (BNIP3) via miR-134-5p, while upregulation of BNIP3 restored mitophagy function in LAMP2A-deficient macrophages. In conclusion, our study demonstrated that deficiency of LAMP2A in macrophages accelerated hypoxia-induced atherosclerosis, partially through the inhibition of BNIP3-mediated mitophagy via miR-134-5p.

AimsRiboflavin (VB2) is primarily utilized as an adjuvant in cancer therapy. This study aims to investigate the preventive and therapeutic effects of VB2 alone on hepatocellular carcinoma (HCC).Main methodsThe preventive and therapeutic efficacy of VB2 against HCC was evaluated using a Hras12V transgenic mouse model of HCC. Initial mechanistic insights were obtained through transcriptome sequencing combined with bioinformatic analyses, and key findings were validated via molecular biology techniques.Key findingsVB2 administration significantly suppressed hepatic tumorigenesis, as evidenced by reductions in liver tumor burden and improved histology. Bioinformatic analysis revealed that VB2-mediated tumor suppression may involve the regulation of multiple metabolic pathways, including fatty acid and amino acid metabolism. Subsequent molecular validation indicated that VB2 enhanced hepatic retinol metabolism by upregulating key metabolic enzymes. It concurrently inhibited hepatocellular proliferation through p21-mediated G1/S phase arrest and suppressed DNA replication by downregulating the Mcm helicase complex. Additionally, VB2 exhibited inhibitory activity against the progression of established tumors, although this effect was not as significant as its suppression of hepatic tumorigenesis. Safety assessments in wild-type C57BL/6 mice revealed no significant treatment-related toxicity.SignificanceTo our knowledge, this study is the first to demonstrate in vivo that VB2 alone can significantly suppress hepatic tumorigenesis by enhancing retinol metabolism and inhibiting cell proliferation pathways, highlighting its potential as a chemopreventive agent for HCC.