Environmentally relevant PFBS exposure triggers colonic inflammation through PPAR-mediated mitochondrial dysfunction...

Perfluorobutane sulfonate (PFBS), a widely used replacement for legacy per- and polyfluoroalkyl substances (PFAS), is increasingly detected in both environmental matrices and human serum. However, its intestinal toxicity remains poorly understood, and effective intervention strategies to mitigate these adverse effects are currently lacking. Here, we demonstrate that environmentally relevant PFBS exposure (0.05 and 0.5 mg/kg) induces colonic inflammation and intestinal barrier disruption in mice, characterized by inflammatory cell infiltration, elevated pro-inflammatory cytokine production, and significantly reduced ZO1 fluorescence intensity and tight junction protein expression. Integrated transcriptomic and network toxicology analyses identified peroxisome proliferator-activated receptors (PPARα/γ) as central molecular targets of PFBS-induced colonic inflammation. Molecular dynamics simulations predicted stable interactions between PFBS and PPARα/γ, while cellular thermal shift assays provided experimental evidence of PFBS target engagement with both receptors. Mechanistically, PFBS stably interacted with PPARα/γ and suppressed their expression, leading to mitochondrial dysfunction, increased ROS accumulation, and cytosolic release of mitochondrial DNA (mtDNA). The released mtDNA subsequently activated the cGAS-STING innate immune signaling pathway, thereby amplifying intestinal inflammatory responses. Importantly, pharmacological activation of the PPAR pathway with bezafibrate effectively alleviated PFBS-induced inflammation, supporting a critical role of PPAR dysregulation in PFBS intestinal toxicity. Collectively, our findings reveal a previously unrecognized PPAR/mitochondria/cGAS-STING signaling axis underlying PFBS-induced colonic inflammation and highlight the potential environmental health risks associated with PFBS as an emerging PFAS substitute.