USP8 promotes the progression of sepsis-induced acute lung injury by interacting with the USP24 to suppress PGC-1α deubiquitination and expression

This is the authors' abstract. We don't add key points for this paper.

Sepsis is a life-threatening condition with high morbidity and mortality, in which acute lung injury (ALI) represents one of the earliest and most severe complications, yet effective therapeutic strategies remain limited. The molecular mechanisms underlying ALI pathogenesis are still incompletely understood. In this study, we identify ubiquitin-specific protease 8 (USP8) as a critical regulator of mitochondrial homeostasis and ferroptosis during sepsis-induced ALI. Mechanistically, USP8 modulates mitochondrial biogenesis and promotes ferroptosis by interfering with the interaction between USP24 and PGC-1α in a manner independent of its deubiquitinase activity. Notably, genetic ablation of USP8 markedly attenuates ALI; however, this protective effect is strictly dependent on the presence of USP24. Collectively, our findings uncover a previously unrecognized regulatory mechanism by which USP8 controls ferroptotic signaling and highlight USP8 and USP24 as potential therapeutic targets for sepsis-associated acute lung injury.