Succinic acid inhibits hepatocyte regenerative signaling via STAT3 SH2-domain engagement

The restoration of liver mass after partial hepatectomy (PH) and split liver transplantation (SLT) relies on efficient liver regeneration, a process highly susceptible to metabolic dysregulation. Although remodeling of the tricarboxylic acid (TCA) cycle is commonly observed during liver injury and regeneration, the specific role of succinic acid remains unclear. Here, we integrated radiomics, transcriptomics, metabolomics, and functional assays to systematically evaluate the association between succinic acid and liver regeneration. Multi-omics analysis of 20 SLT patients demonstrated that elevated succinic acid levels were strongly associated with impaired regenerative outcomes, and weighted gene co-expression network analysis identified the TCA cycle as a key regeneration-associated metabolic module. In a 70% PH mouse model, succinic acid administration was associated with reduced survival and decreased hepatocyte proliferation, consistent with impaired liver regeneration. Mechanistically, succinic acid exhibited distinct effects in different cell types: in macrophages, it enhanced inflammatory activation and increased interleukin-6 (IL-6) secretion, whereas in hepatocytes it reduced IL-6-induced STAT3 phosphorylation and downstream regenerative signaling. Furthermore, molecular docking, molecular dynamics simulations, and surface plasmon resonance assays supported an interaction between succinic acid and the STAT3 SH2 domain, providing structural evidence consistent with modulation of STAT3 signaling. Collectively, these findings suggest that succinic acid may function as an immunometabolic regulator that contributes to impaired liver regeneration by altering macrophage-derived IL-6 signaling and hepatocyte STAT3 activation. These findings also support further investigation of the succinic acid-STAT3 axis as a potential therapeutic target for promoting liver regeneration following hepatic injury or resection.