Hydrogen attenuates sepsis-related liver injury by promoting PINK1/Parkin-mediated mitophagy

Background Sepsis-related liver injury (SRLI) is closely associated with poor outcomes in patients with sepsis. Hydrogen (H 2 ) has a hepatoprotective effect in sepsis, but its specific mechanism remains unclear. This study aimed to explore whether 67% H 2 treatment mitigates SRLI through promoting mitophagy and inhibiting the cGAS–STING pathway. Methods Male C57BL/6 J mice underwent cecal ligation and puncture to establish a sepsis model. To evaluate the effect of 67% H 2 on SRLI, 7-day survival rates, liver function, and liver hematoxylin and eosin staining were measured. Electron microscopy was used to observe mitochondrial autophagosomes. Western blot and immunofluorescence were used to detect the levels of mitophagy-related proteins. Additionally, the autophagy inhibitor 3-MA was administered to observe whether the therapeutic effect of inhalation of 67% H 2 could be reversed. Finally, indicators of the cGAS–STING pathway were examined to investigate how 67% H 2 affects the downstream mechanism of mitophagy. Results Inhalation of 67% H₂ effectively improved the survival rate of septic mice, alleviated liver dysfunction, increased mitophagy, and inhibited the cGAS–STING pathway. However, administration of 3-MA reversed the therapeutic effects of H₂. Conclusions H 2 exerted a protective effect on SRLI, and its mechanism was related to promoting PINK1/Parkin-mediated mitophagy and inhibiting the cGAS–STING pathway.