Phospholipase A2 group IIA activates Indoleamine 2,3-dioxygenase 1 to drive the progression of pulmonary fibrosis.

Phospholipase A2 Group IIA (PLA2G2A), a secretory member of the phospholipase family, plays key roles in various physiological processes across multiple metabolic tissues. While PLA2G2A is expressed in lung epithelial cells and fibroblasts, its functions in lung injury and fibrosis remain poorly understood. In this study, we characterized the critical role of PLA2G2A in pulmonary fibrosis (PF) in both human patients and bleomycin (BLM)-induced PF mouse models. We found that PLA2G2A is significantly upregulated in the fibrotic lungs of both PF patients and mice, with its expression positively correlating with fibrotic gene markers. Functionally, PLA2G2A induced pyroptosis in lung epithelial cells, leading to mitochondrial damage, activation of the STING-NLRP3-GSDMD axis, and increased expression of α-SMA and COL1A1 in fibroblasts. Additionally, recombinant PLA2G2A protein directly induced the expression of IDO1 and α-SMA in human lung fibroblasts (HLFs) and primary mouse lung fibroblasts (MLFs). Mechanistically, PLA2G2A appears to alter lipid metabolism either directly or by activating IDO1, which exacerbates PF through AHRR-mediated inhibition of AHR. For therapeutic strategy, we administered Varespladib (a PLA2G2A inhibitor) and Indoximod (the selective IDO1 inhibitor) to the animals, both of which were found to mediate the progression of PF. Our findings suggest that PLA2G2A plays a central role in pro-fibrotic processes by modulating epithelial cells and fibroblasts, thereby promoting extracellular matrix production. Given its involvement in PF pathogenesis, PLA2G2A may serve as a potential therapeutic target for PF, with PLA2G2A inhibitors offering a promising strategy for clinical treatment.