Biomedical subjects
Publications and source records attributed to Zihui Deng.
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BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of sepsis. However, human genetic evidence linking mitochondria-related genes to sepsis susceptibility remains limited. This study aimed to identify mitochondria-related genes associated with sepsis risk using a multi-omics Mendelian randomization framework. METHODS: Summary-data-based Mendelian randomization (SMR) was applied using sepsis genome-wide association study (GWAS) summary statistics from the UK Biobank and FinnGen databases. Expression, methylation, single-cell, and protein quantitative trait loci (QTLs) were used as genetic instruments. Colocalization analyses were conducted to evaluate whether SMR associations were driven by shared genetic variants. Expression of prioritized candidate genes was further examined in clinical septic samples, and correlations with disease severity (SOFA scores) were assessed. RESULTS: SMR analysis prioritized 13 mitochondria-related genes associated with sepsis risk. Immune cell-specific eQTL analysis suggested that genetically predicted SURF1 expression in memory B cells and naïve T cells was associated with sepsis risk. Differential expression of 12 candidate genes was confirmed in septic patients by qPCR, and PPOX expression showed a negative correlation with SOFA scores. Integration of mQTL and eQTL data supported a regulatory relationship between methylation at cg06661924 and AK4 expression. Increased genetically predicted AK4 expression was associated with higher sepsis risk (OR = 1.21, 95% CI 1.02-1.42). Protein-level analysis identified DUT as a potential sepsis-associated candidate, with consistent evidence across streptococcal and pneumococcal septicemia subtypes. Subtype analyses also suggested heterogeneous genetic signals across different sepsis subtypes. CONCLUSION: This study prioritized several mitochondria-related genes associated with sepsis susceptibility based on human genetic evidence. These findings provide candidate targets for further mechanistic and translational investigation.
Mesenchymal stem cells-derived exosomes (MSCs-Exo) constitute critical mediators of intercellular communication between stem cells and other cell types. Among these, exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs-Exo) have attracted considerable attention owing to their potent immunomodulatory capacity, low surface antigenicity, and favorable biosafety profile. Accumulating evidence indicates that HUMSCs-Exo can attenuate ferroptosis in target tissues across a spectrum of pathological conditions, including inflammatory bowel disease and viral cardiomyopathy, thereby mitigating tissue injury, improving organ function, and prolonging host survival. Nevertheless, the regulatory effects of HUMSCs-Exo on sepsis-associated liver injury (SALI) and hepatocellular ferroptosis, as well as the underlying molecular mechanisms, remain largely undefined. In this study, we identified pronounced differential gene expressions between control and septic mice hepatocytes, particularly within pathways related to iron metabolism, lipid metabolism, and ferroptosis. Building on these findings, we systematically characterized the dynamic progression of hepatocyte ferroptosis in septic mice through integrated in vivo and in vitro experiments, demonstrating a strong positive correlation between ferroptotic activity and the severity of liver injury. Using wild-type male C57BL/6J mice and the murine normal hepatocyte cell line NCTC1469, we further demonstrated that HUMSCs-Exo markedly upregulate the expression of FPN, xCT, GPX4, and FTH1 while concomitantly downregulating ACSL4 and TFRC. These molecular alterations reduced intracellular lipid peroxidation and labile iron accumulation, thereby robustly attenuating sepsis-induced hepatocyte ferroptosis and conferring significant hepatoprotective effects. Finally, these findings were validated in the immortalized human normal hepatocyte cell line THLE-2, in which HUMSCs-Exo similarly suppressed lipopolysaccharide-induced ferroptosis and cellular injury by modulating intracellular lipid peroxide and free iron levels. Collectively, our results demonstrate that HUMSCs-Exo exert potent inhibitory effects on sepsis-induced hepatocyte ferroptosis and confer protection against liver injury, primarily through the restoration of intracellular iron homeostasis and the suppression of lipid peroxidation. This study provides a novel therapeutic strategy for the treatment of SALI and ferroptosis.