Environmentally relevant PFBS exposure triggers colonic inflammation through PPAR-mediated mitochondrial dysfunction and cGAS–STING activation
7 affiliations
- 1Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Department of General & Neonatal Surgery, Children’s Hospital of Chongqing Medical University, Chongqing, 401120, China
- 2Department of Pediatric Infectious Diseases, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- 3School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
- 4Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai, 200062, China
- 5Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, USA
- 6Department of General & Neonatal Surgery, Children’s Hospital of Chongqing Medical University, Chongqing, 401120, China; Corresponding authors.
- 7Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Corresponding authors.
Abstract
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.
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BibTeX
@article{chen2026environmentally,
title = {{Environmentally relevant PFBS exposure triggers colonic inflammation through PPAR-mediated mitochondrial dysfunction and cGAS–STING activation}},
author = {Minming Chen and Xianting Jiao and Chenyin Dong and Wenwen Qu and Liping Feng and Yi Wang and Fei Li and Yongjie Liu},
journal = {Ecotoxicology and Environmental Safety},
year = {2026},
month = oct,
doi = {10.1016/j.ecoenv.2026.120967},
url = {https://doi.org/10.1016/j.ecoenv.2026.120967},
note = {CC BY},
}
RIS
TY - JOUR
TI - Environmentally relevant PFBS exposure triggers colonic inflammation through PPAR-mediated mitochondrial dysfunction and cGAS–STING activation
AU - Minming Chen
AU - Xianting Jiao
AU - Chenyin Dong
AU - Wenwen Qu
AU - Liping Feng
AU - Yi Wang
AU - Fei Li
AU - Yongjie Liu
PY - 2026
DA - 2026/10/26
JO - Ecotoxicology and Environmental Safety
DO - 10.1016/j.ecoenv.2026.120967
UR - https://doi.org/10.1016/j.ecoenv.2026.120967
AB - 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.
SN - 0147-6513
SN - 1090-2414
ER -