RUNX2 and USP16 stabilize MFRN2 to maintain pulmonary epithelial barrier integrity in sepsis-induced acute lung injury

Sepsis is a life-threatening condition characterized by high morbidity and mortality, with acute lung injury (ALI) being one of its most common and severe complications. However, the precise molecular mechanisms underlying ALI remain unclear. Here, we identify RUNX2 as a critical mediator of epithelial injury in sepsis-induced ALI, independent of macrophage activation. Mechanistically, lipopolysaccharide (LPS) stimulation enhances the binding of RUNX2 to the USP16 promoter, thereby transcriptionally activating USP16 expression. This activation reduces K27-linked ubiquitin chains on mitoferrin-2 (MFRN2) at lysine 97, leading to mitochondrial iron dyshomeostasis and promoting epithelial ferroptosis. Moreover, aryl hydrocarbon receptor (AHR) interacts with RUNX2 to suppress its activation, thereby attenuating epithelial apoptosis. Collectively, our study uncovers a previously unrecognized mechanism by which LPS triggers epithelial cell death in ALI and suggests that targeting RUNX2 transcriptional activation may enhance epithelial resistance to injury induced by sepsis.