Granzyme A participates in intestinal inflammation induced by PFOA through affecting PAR1/β-catenin/TBX3/IL24 pathway.

Perfluorooctanoic acid (PFOA) has been associated with damage to multiple organs, and its effects on the gastrointestinal system have attracted increasing attention. However, the mechanism underlying PFOA-induced intestinal toxicity remains unclear. In this study, we found that PFOA disrupted the intestinal barrier and induced intestinal inflammation in mice, accompanied by increased GzmA expression. Mechanistically, GzmA upregulation promoted intestinal inflammation through the GzmA-PAR1 signaling axis, which enhanced the interaction between caveolin-1 and β-catenin and facilitated the nuclear accumulation of β-catenin. Nuclear β-catenin subsequently upregulated TBX3, which bound to an upstream regulatory of IL24 and promoted IL24 expression following PFOA exposure. To validate the role of GzmA, we knocked down GzmA in normal colonic epithelial cells (NCM460). The results confirmed that GzmA upregulated IL24 expression through the PAR1/β-catenin/TBX3 pathway following PFOA exposure. These findings provide mechanistic insight into PFOA-induced colonic inflammation and highlight the potential utility of this toxicant-based model for investigating molecular targets relevant to intestinal inflammatory diseases.