OTUD1 inhibits macrophage ferroptosis via regulation of AMPK and GSK3β/β-catenin signaling pathways exerting protective effects in sepsis-induced acute lung injury.

Sepsis is a life-threatening organ dysfunction caused by dysregulated inflammatory and immune responses to infection. Its global incidence and mortality remain high, posing a severe threat to public health. Acute lung injury (ALI) is a common and serious complication of sepsis. Current understanding of the pathogenesis and effective therapeutic strategies for sepsis-induced acute lung injury (SI-ALI) remains insufficient. This study aims to investigate the role and underlying mechanisms of the deubiquitinase OTUD1 in sepsis-induced pulmonary injury. Using a mouse model of sepsis-induced lung injury combined with genetic knockout techniques and ferroptosis inhibitors, we systematically analyzed the protective effects of OTUD1 in sepsis-related lung damage and explored the regulatory roles of AMPK and GSK3β/β-catenin signaling pathways. Results demonstrated that OTUD1 gene deletion exacerbated lung tissue damage and inflammatory responses in septic mice while increasing ferroptosis levels; pretreatment with the ferroptosis inhibitor Ferrostatin-1 significantly ameliorated these effects. Further mechanistic studies revealed that OTUD1 may regulate ferroptosis levels in lung tissue by modulating the activation status of AMPK and GSK3β/β-catenin pathways. Specifically, OTUD1 may remove K63-linked ubiquitin chains from AMPK, altering its protein conformation and subsequently promoting AMPK phosphorylation to regulate the GSK3β/β-catenin signaling cascade. Collectively, this study provides the first systematic elucidation of OTUD1's protective role in sepsis-induced lung injury and its relationship with ferroptosis, offering novel molecular targets and theoretical foundations for the treatment of sepsis-associated pulmonary damage.