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<p>Sepsis-associated acute kidney injury (SA-AKI) represents a prevalent complication in critically ill patients, and its molecular mechanisms remain incompletely understood. Circular RNAs (circRNAs) have been increasingly implicated in the pathogenesis of multiple diseases; however, the function and mechanism of circGAB1 in SA-AKI remain largely unknown. Differentially expressed circRNAs in SA-AKI were identified from the Gene Expression Omnibus database (dataset GSE232404), and circGAB1 expression was confirmed by quantitative real-time polymerase chain reaction. Its stability and subcellular localization were assessed using RNase R digestion, actinomycin D assay, and fluorescence in situ hybridization. circGAB1 was knocked down with short hairpin RNA, and its effects on autophagy, cell viability, and apoptosis were evaluated using Cell Counting Kit-8, Western blot, monodansylcadaverine staining, lactate dehydrogenase release, and flow cytometry. Interactions among circGAB1, ELAV-like RNA-binding protein 1 (ELAVL1), and High Mobility Group Box 3 (HMGB3) were examined by RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assays. In vivo, adenovirus-mediated knockdown or overexpression was employed to assess the role of the circGAB1/ELAVL1/HMGB3 axis in autophagy, the β-catenin pathway, and renal function. Analysis of the public GEO dataset revealed that circGAB1 was significantly upregulated in SA-AKI samples, and its high expression was also verified in SA-AKI model cells. Additionally, circGAB1 exhibited a nucleocytoplasmic subcellular localization pattern. In SA-AKI mice, knockdown of circGAB1 inhibited autophagy, reduced cellular damage, and improved renal function. Mechanistically, circGAB1 bound to ELAVL1 to enhance HMGB3 mRNA stability, thereby activating the β-catenin pathway and promoting autophagy. Overexpression of ELAVL1 or HMGB3 reversed the suppressive effects of circGAB1 knockdown on autophagy and the β-catenin pathway. circGAB1 enhances HMGB3 mRNA stability by binding to ELAVL1, thereby activating the β-catenin pathway and autophagy to promote SA-AKI. Targeting circGAB1 may provide a new strategy for SA-AKI treatment.</p>

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circGAB1 Activates Autophagy to Promote Sepsis-Associated Acute Kidney Injury by Interacting with ELAVL1 to Activate the HMGB3/β-catenin Signaling Pathway​

  • 期刊论文

  • 发表日期：

    2026年7月10日

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  • LinLin Yue,
  • XiaoFeng Liu,
  • JianHua Li,
  • Xin Liu,
  • JiYing Lai,
  • Jie Wang,
  • ChaoYu Wu,
  • ZhiYuan Zhang,
  • QianDuo Li,
  • Feng Chen

摘要

Sepsis-associated acute kidney injury (SA-AKI) represents a prevalent complication in critically ill patients, and its molecular mechanisms remain incompletely understood. Circular RNAs (circRNAs) have been increasingly implicated in the pathogenesis of multiple diseases; however, the function and mechanism of circGAB1 in SA-AKI remain largely unknown. Differentially expressed circRNAs in SA-AKI were identified from the Gene Expression Omnibus database (dataset GSE232404), and circGAB1 expression was confirmed by quantitative real-time polymerase chain reaction. Its stability and subcellular localization were assessed using RNase R digestion, actinomycin D assay, and fluorescence in situ hybridization. circGAB1 was knocked down with short hairpin RNA, and its effects on autophagy, cell viability, and apoptosis were evaluated using Cell Counting Kit-8, Western blot, monodansylcadaverine staining, lactate dehydrogenase release, and flow cytometry. Interactions among circGAB1, ELAV-like RNA-binding protein 1 (ELAVL1), and High Mobility Group Box 3 (HMGB3) were examined by RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assays. In vivo, adenovirus-mediated knockdown or overexpression was employed to assess the role of the circGAB1/ELAVL1/HMGB3 axis in autophagy, the β-catenin pathway, and renal function. Analysis of the public GEO dataset revealed that circGAB1 was significantly upregulated in SA-AKI samples, and its high expression was also verified in SA-AKI model cells. Additionally, circGAB1 exhibited a nucleocytoplasmic subcellular localization pattern. In SA-AKI mice, knockdown of circGAB1 inhibited autophagy, reduced cellular damage, and improved renal function. Mechanistically, circGAB1 bound to ELAVL1 to enhance HMGB3 mRNA stability, thereby activating the β-catenin pathway and promoting autophagy. Overexpression of ELAVL1 or HMGB3 reversed the suppressive effects of circGAB1 knockdown on autophagy and the β-catenin pathway. circGAB1 enhances HMGB3 mRNA stability by binding to ELAVL1, thereby activating the β-catenin pathway and autophagy to promote SA-AKI. Targeting circGAB1 may provide a new strategy for SA-AKI treatment.