GDF15 attenuates sepsis-associated liver injury by regulating macrophage polarization via the AMPK/PKM2/HIF-1a pathway.

Sepsis-associated liver injury (SALI) is a common and severe complication of sepsis, and effective clinical treatment strategies are still lacking. Macrophages, a highly heterogeneous population of immune cells, play a key role in triggering and regulating the cytokine storm. Enhanced glycolysis is the key driver behind the increased proportion of M1 macrophages and the elevated release of pro-inflammatory factors. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine with anti-inflammatory and tissue repair functions. However, the specific role and mechanism of GDF15 in SALI remain unclear. In this study, a mouse SALI model and a macrophage M1 polarization model were established using lipopolysaccharide (LPS). Recombinant GDF15 protein was used to investigate its role and related mechanisms. The results showed that GDF15 markedly alleviated liver injury and effectively suppressed the release of pro-inflammatory cytokines. In both in vivo and in vitro experiments, GDF15 promoted the polarization of macrophages from the M1 to the M2 phenotype. Mechanistically, GDF15 inhibits the pyruvate kinase M2 (PKM2)/hypoxia inducible factor 1α (HIF-1α) axis-mediated glycolysis and macrophage M1 polarization by activating AMP-activated protein kinase (AMPK). These findings indicate that GDF15 is a potential target for the clinical prevention and treatment of SALI.