Environmentally relevant concentrations of PFDA exacerbate inflammatory bowel disease through impairing macrophagic efferocytosis of apoptotic intestinal epithelial cells

Perfluorodecanoic acid (PFDA), a member of the per- and polyfluoroalkyl substances (PFAS) family, is widely used in industrial and consumer products. The compound is bioaccumulative, raising significant health concerns regarding the pathological consequences of human exposure, which primarily occurs through contaminated drinking water and dietary sources. Previous studies have shown that PFDA exposure has adverse associations with inflammatory bowel disease (IBD). However, the mechanism underlying this association is unclear. This study aims to investigate the impact of PFDA on IBD progression, elucidate the underlying mechanisms, and identify potential therapeutic targets. In this study, we utilized population-based analysis, RNA-sequencing, in vitro and in vivo experiments to elucidate the mechanisms underlying PFDA-induced exacerbation of IBD and explore potential interventions. Our study reveals that PFDA exacerbates IBD progression by inducing macrophage senescence, which impairs efferocytosis of apoptotic intestinal epithelial cells. Notably, metformin counteracts this PFDA-driven pathology. These findings establish the pro-inflammatory mechanism of PFDA and highlight metformin as a potential therapeutic agent, providing new insights for PFAS risk assessment and disease management. • Environmental PFDA exposure impairs macrophage efferocytosis of apoptotic intestinal epithelial cells. • PFDA induces macrophage senescence at environmentally relevant concentrations. • PFDA-activated NF-κB signaling drives efferocytosis impairment and macrophage senescence. • Metformin reverses PFDA-induced macrophage senescence and efferocytosis dysfunction. • Metformin is a therapeutic candidate for PFDA-exacerbated inflammatory bowel disease.