Xunde Xian

Background: ATP‐binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux, yet its role in inflammatory bowel disease (IBD) remains incompletely understood. This study investigated the consequences of intestinal epithelial cholesterol accumulation—primarily driven by ABCA1 deficiency—on colonic inflammation and the underlying molecular mechanisms. Methods: ABCA1 knockout (KO) and wild‐type (WT) Syrian golden hamsters were fed a high‐cholesterol high‐fat diet for 12 weeks. Colon specimens were analyzed for pathological changes, inflammatory markers, cholesterol accumulation, and gene expression profiles. Furthermore, in vitro experiments were performed using the human colon epithelial cell line Caco‐2. Results: ABCA1 deficiency, in the context of a high‐cholesterol high‐fat diet, triggered significant colonic inflammation in KO hamsters, characterized by epithelial damage, inflammatory cell infiltration, and elevated pro‐inflammatory cytokine levels. These pathological changes were associated with impaired mucosal barrier integrity, a four‐fold increase in epithelial cholesterol accumulation, and reduced E‐cadherin, ZO‐1 and occludin expression. Furthermore, ABCA1 deficiency promoted oxidative stress and induced marked remodeling of the gut microbiota. Conclusions: Our findings establish a pathogenic role for ABCA1 deficiency in driving colonic epithelial injury and inflammation, suggesting that ABCA1 may play an important role in the pathogenesis of IBD.

Acute myocardial infarction (MI) is a leading cause of mortality worldwide. Although reperfusion restores coronary blood flow, it paradoxically induces secondary injury that limits therapeutic benefits, and effective interventions for myocardial ischemia/reperfusion injury (MI/RI) remain lacking. Here, we identify scavenger receptor class A member 3 (SR‐A3) as a previously unrecognized cardioprotective factor that plays a central regulatory role in ischemic injury. SR‐A3 was significantly downregulated in myocardial tissues from MI/RI patients. Global or cardiomyocyte‐specific deletion of SR‐A3 exacerbated MI/RI‐induced cardiac damage, whereas AAV9‐mediated overexpression alleviated myocardial injury and improved cardiac function. Notably, SR‐A3 expression in cardiomyocytes underwent the most dramatic reduction upon I/R stress, underscoring its critical role in the injured myocardium. Mechanistically, SR‐A3 interacts with ubiquitin‐specific peptidase 18 (USP18) to suppress interferon‐stimulated gene 15 (ISG15)‐dependent ISGylation, thereby negatively regulating activation of the STING signaling pathway and its downstream innate immune inflammatory cascades. Treatment with Selonsertib, an ASK1 inhibitor that increased USP18 abundance in our MI/RI model, recapitulated the cardioprotective effects, highlighting the translational potential of targeting this signaling axis. Collectively, our findings uncover a novel SR‐A3/USP18/ISG15/STING regulatory pathway governing innate immune activation in MI/RI and position SR‐A3 as a promising therapeutic target for ischemic heart disease.

Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in pati

Angiopoietin-like protein 3 (Angptl3), a factor secreted by the liver, inhibits lipoprotein lipase and other lipases by forming a complex with Angptl4 and 8. However, whether inhibition of Angptl3 can alleviate hepatic lipid accumulation and atherosclerosis remains unclear. Therefore, this study explored the effect of small interfering RNA (siRNA)-based inactivation of Angptl3 on metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis in male LDLR-deficient hamsters. Recombinant adeno-associated virus serotype 9 (AAV9) encoding Angptl3-siRNA or empty AAV (AAV9-null) were injected into male 4-month-old LDLR^−/− hamsters via the jugular vein. Subsequently, all hamsters were administered with a 16-week high-fat diet (HFD) feeding to induce atherosclerosis. RT-PCR and pathological analysis were used to investigate the mechanism of hepatic lipid accumulation and detect atherosclerotic plaque formation in the heart and aorta. On HFD, Angptl3-siRNA-treated hamsters displayed significantly decreased plasma triglyceride (TG), total cholesterol, high-density lipoprotein-cholesterol, and glucose levels, compared with the AAV9-null hamsters. FPLC analysis further revealed a marked reduction of TG and cholesterol contents in VLDL/LDL fractions. Plasma apolipoprotein analysis showed relatively lower ApoB/ApoE levels and higher ApoA1 levels. Moreover, Angptl3-siRNA markedly accelerated the clearance of triglyceride-rich lipoproteins in LDLR^−/− hamsters. Consistently, results from hepatic lipid extraction, Oil Red O and Sirius Red staining demonstrated that Angptl3-siRNA reduced hepatic lipid accumulation and ameliorated HFD-induced MAFLD. RT-PCR revealed a dramatic decrease in the expression of Acc1, Fasn, Srebp1c, Cd36, Fatp1, Tgfβ, Cd68, Tnfa, and Col1a1 as well as a marked increase in Abcg5, Abcg8, Ppara, and Cpt1 expression, which participated in fatty acid synthesis and oxidation, cholesterol synthesis and efflux, inflammation and fibrosis. Pathological analysis indicated that Angptl3-siRNA attenuated the formation of atherosclerotic plaques in the aortic root and aorta when compared with the control group. These findings demonstrated that siRNA-based inactivation of Angptl3 alleviated MAFLD and atherosclerosis induced by HFD in LDLR^−/− hamsters, which further confirmed that inhibition of Angptl3 may provide a novel therapeutic approach for atherosclerosis by reducing hyperlipidemia and hepatic lipid accumulation. The online version contains supplementary material available at 10.1186/s12944-026-02916-3.

Background and Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a critical pathological stage that can progress to liver fibrosis and hepatocellular carcinoma, and its development is closely associated with dysregulation of the hepatic immune microenvironment, in which macrophages make a crucial contribution. However, the precise mechanisms mediated by macrophages underlying the pathogenesis of this disease remain incompletely understood. Approach and Results: In the present study, we demonstrate that under MASLD conditions, KIF13B expression is markedly downregulated in monocyte-derived macrophages, and deletion of myeloid-derived Kif13b predisposes mice to diet-induced MASLD. Mechanistically, Kif13b deficiency impairs proteasome-dependent degradation of the glycosyltransferase STT3A in macrophages, thereby enhancing cathepsin D (CTSD) glycosylation and secretion to promote lipid accumulation and inflammatory responses in livers. Further analyses reveal that the detrimental effects of CTSD depend on its interaction with the hepatocyte membrane protein Thrombospondin 1 (THBS1). In addition, we identify the transcription factor ZNF384 as a potential upstream regulator of KIF13B gene through directly binding to its promoter for the transcriptional activation, which expression is also significantly downregulated in the context of MASLD. Conclusions: Collectively, our study establishes a novel regulatory axis, ZNF384/KIF13B/STT3A/CTSD/THBS1, essential for macrophage-hepatocyte crosstalk during MASLD progression and provides potential therapeutic targets for the treatment of MASLD.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide, with plaque instability being a major culprit. Phenotypic switching of vascular smooth muscle cells (VSMCs) is a central event in atherosclerosis, driving both plaque progression and stability, yet the underlying mechanisms are incompletely understood, limiting drug development targeting this process. Kinesin family member 13B (KIF13B) has been implicated in vascular biology, but its function in VSMCs is unknown. Here, we demonstrate that VSMC-specific deletion of Kif13b in mice overexpressing proprotein convertase subtilisin/kexin type 9 (PCSK9) exacerbates lesion development and impairs plaque stability, characterized by thinner fibrous caps and increased inflammation. Mechanistically, we determined that KIF13B facilitated the ubiquitination and proteasomal degradation of Krüppel-like factor 4 (KLF4) through the potassium channel tetramerization domain–containing 10–dependent (KCTD10-dependent) pathway. This KIF13B/KCTD10 axis reduced KLF4 protein levels, thereby inhibiting the proinflammatory responses and fibroblast-like transition of VSMCs to preserve their contractile phenotype. Importantly, the adverse effects of Kif13b deficiency on atherogenesis were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone. Our results unveil a VSMC-specific atheroprotective role for KIF13B, define the KIF13B/KCTD10/KLF4 pathway as a key regulatory axis governing VSMC fate and plaque stability, and validate the therapeutic potential of KIF13B for treating advanced atherosclerosis.

Sepsis-induced cardiac dysfunction (SICD) is a major contributor to mortality in sepsis. Kinesin family member 13B (KIF13B) has been identified as a critical protective factor for metabolic disorder and cardiovascular disease; however, the role of KIF13B in SICD remains unknown. After introducing lipopolysaccharide or cecal ligation and puncture surgery to wild-type ( WT ) and global Kif13b knockout ( Kif13b ^−/− ) mice combined with lipopolysaccharide-treated neonatal rat cardiomyocytes, we found that KIF13B expression levels were markedly down-regulated in septic hearts and cardiomyocytes. Kif13b deletion exacerbated SICD progress with reduced cardiac contractile function and resulted in increased mortality, accompanied by promoted lipid accumulation, fibrosis, and mitochondrial impairment. Mechanistically, the loss of KIF13B enhanced the lysosomal degradation of the lipid-droplet-associated protein perilipin 5 (PLIN5), thus disrupting the mitochondrial localization of PLIN5 and then impairing cardiac lipid homeostasis and proper mitochondrial function. Nevertheless, cardiac-directed AAV9- PLIN5 gene therapy sufficiently corrected cardiac dysfunction, inhibited lipid accumulation, and reduced oxidative stress in Kif13b ^−/− mice with SICD. In summary, these findings provide a new insight into the molecular mechanism underlying the pathogenesis of SICD, highlighting the KIF13B/PLIN5 axis as a potential therapeutic target for the treatment of SICD.