RP105 exerts hepatoprotective effects in sepsis by modulating the SOCS2/JAK2/STAT3 signaling pathway

Sepsis‑induced liver injury increases mortality through inflammatory dysregulation. Although Radioprotective 105 (RP105) modulates inflammation, its role in septic liver injury remains unclear. The present study investigates the mechanism of RP105 in sepsis‑driven hepatic damage. Sepsis was induced in RP105 knockout (KO) and wild‑type (WT) mice via cecal ligation and puncture (CLP). Liver injury was assessed by serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), histology (H&E), inflammatory markers (anti‑myeloperoxidase, F4/80, IL‑1β, IL‑6 and TNF‑α) and apoptosis markers (Caspase‑3, BAX/BCL‑2 ratio, GADD45A and PUMA). RNA sequencing identified key differentially expressed genes. RP105‑suppressor of cytokine signaling (SOCS) 2 interaction was validated by co‑immunoprecipitation (Co‑IP) and JAK2/STAT3 pathway activity was measured by western blotting. Lipopolysaccharide‑stimulated RP105‑KO macrophages were used <i>in vitro</i>. RP105‑KO mice exhibited exacerbated liver injury post‑CLP, evidenced by significantly elevated ALT/AST (P<0.001), expanded hepatic necrosis (P<0.001), increased inflammatory infiltration (P<0.001), upregulated pro‑inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α; P<0.001) and enhanced Caspase‑3 expression (P<0.001). RNA‑seq identified SOCS2 as a key RP105‑regulated DEG (fold change >2.0; FDR <0.05). Co‑IP confirmed RP105‑SOCS2 binding in WT liver which was absent in KO mice. SOCS2 protein remained decreased in KO + CLP vs. WT (P<0.001). RP105 deletion activated JAK2/STAT3 signaling <i>in vivo</i> and <i>in vitro</i> (P<0.001). RP105 protects against septic liver injury by binding SOCS2 to inhibit JAK2/STAT3 signaling, thereby attenuating inflammation and apoptosis. The present study is the first to demonstrate the RP105‑SOCS2 interaction in septic liver injury, revealing the RP105/SOCS2 axis as a potential therapeutic target.