The mechanism of SOX4/IGF2BP3/TRIB3 axis inhibiting autophagy and aggravating liver injury in sepsis.

Authors

Wenjun Zhao, Jing Zhang, Liang Zhang, Erchun Hong, Min Shao

Published in

Biochimica et biophysica acta. Molecular cell research. Pages 120208. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Sepsis-associated liver injury (SALI) is a serious complication with limited treatment options. While protective autophagy is often suppressed in sepsis, the underlying mechanisms remain unclear. This study investigated whether the SOX4/IGF2BP3/TRIB3 pathway contributes to liver dysfunction by suppressing cytoprotective autophagy. In vitro experiments were performed using LPS-treated mouse primary hepatocytes, with measurements of SOX4, IGF2BP3, and TRIB3 expression by RT-qPCR and Western blot, cell viability by CCK-8, autophagic flux by mRFP-GFP-LC3 probe, and molecular interactions via luciferase reporter, ChIP, RIP, and RNA stability assays. In vivo, a murine sepsis model was established by cecal ligation and puncture. Clinically, mRNA levels of SOX4, IGF2BP3, and TRIB3 were measured in peripheral blood mononuclear cells from sepsis patients and correlated with clinical scores and outcomes. We found that the SOX4/IGF2BP3/TRIB3 axis was upregulated in septic hepatocytes, and its knockdown alleviated LPS-induced injury and impaired autophagic flux. SOX4 transcriptionally activated IGF2BP3, which stabilized TRIB3 mRNA in an m6A-dependent manner. Rescue experiments confirmed that this axis exacerbated LPS-induced hepatocyte injury by suppressing autophagic flux. Inhibition of SOX4 or IGF2BP3 alleviated liver injury and improved survival in septic mice. Clinically, circulating SOX4, IGF2BP3, and TRIB3 levels stratified the presence and severity of SALI and provided high-precision prognostic information. In conclusion, in SALI, SOX4 upregulates IGF2BP3, which stabilizes TRIB3 mRNA in an m6A-dependent manner. Accumulation of TRIB3 protein suppresses cytoprotective autophagy, ultimately leading to hepatocyte death and liver dysfunction.

PMID:
42580595
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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