Environmental exposure to perfluorooctanoic acid promotes early gastric carcinogenesis via PPAR-γ-mediated ferroptosis.

Perfluorooctanoic Acid (PFOA) has gained our attention for it is resistant to natural degradation and can migrate over long distances. We have already found that PFASs were related to gastric cancer in previous work. However, the systematic evidence on the gastric toxicity of PFOA and its mechanisms remains scarce. In this study, network toxicology pinpointed the peroxisome proliferator-activated receptor (PPAR) pathway as the pivotal driver between PFOA exposure and gastric cancer progression. In the cell experiments, PPAR inhibitor (10 μM) and ferroptosis inhibitor (2 μM) protect gastric cells from ferroptosis induced by PFOA (200 ng L-1). In the animal experiments, we set 3 PFOA concentrations (34.85 ng kg-1 day-1,1mg kg-1 day-1, 2.5 mg kg-1 day-1). Based on differential metabolic rate, the environmental dosage of PFOA in human was transferred to the lowest mice dosage. The RNA-seq analysis identified PPAR-γ as a differentially expressed gene. Compared with the normal group, the PFOA-L group of PPAR-γ decreased by 31.6%, the PFOA-M group of PPAR-γ decreased by 14.4%, and the PFOA-H group decreased by 46.8%. By organoid experiments, 5 days PFOA induced PPAR-γ downregulation and the increase of cancer marker P53. We elucidate that PFOA disrupts the PPAR-γ axis to induce gastric cancer progression, highlighting an overlooked gastric liability in PFOA health risk assessments.