Peripheral Circulating Exosomes Induce Sepsis-associated Liver Injury by Up-regulating STAT1 to Promote Autophagy and Regulating the SLC7A11-GSH-GPX4 Axis to Promote Ferroptosis

Peripheral exosomes have been implicated in the pathogenesis of multiple organ dysfunction during sepsis. However, their role in sepsis-associated liver injury (SALI) remains unclear. This study aimed to investigate the effects of circulating exosomes on hepatic injury and to elucidate the underlying molecular mechanisms of SALI. A murine sepsis model was established via intraperitoneal injection of lipopolysaccharide (LPS). Peripheral exosomes were isolated and co-cultured with murine hepatocytes (AML12 cells). RNA sequencing identified Signal transducer and activator of transcription 1 (STAT1) as a key regulator in exosome-induced liver injury. Since STAT1 functions upstream of the ferroptosis-related solute carrier family 7 member 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, further in vivo and in vitro experiments were conducted to clarify its mechanistic role. In vitro, exosomes derived from septic mice enhanced inflammatory responses in AML12 cells via STAT1-mediated autophagy and modulation of the SLC7A11-GSH-GPX4 axis, leading to ferroptosis. Inhibition of STAT1 abrogated these effects, whereas STAT1 overexpression potentiated them. In vivo, septic exosomes (sep-Exo) induced liver injury in mice, while suppression of STAT1 abolished the regulatory effects of sep-Exo on ferroptosis, autophagy, and hepatic inflammation. Our findings reveal a novel mechanism underlying SALI, whereby peripheral exosomes upregulate STAT1 to induce autophagy and modulate the SLC7A11-GSH-GPX4 axis, thereby promoting ferroptosis and hepatic inflammation during sepsis.