PLA2G2A promotes macrophage pro-fibrotic polarization through the MAT2A/SAM–SCD1 axis and induces reciprocal paracrine signaling with stromal cells

Zhuofan Yang, Xiaofei Xie, Jinjuan Wen, Shaoru Jiang
In: Journal of Radiation Research and Applied Sciences · 2026 · vol. 19(4) , pp. 102774 · doi:10.1016/j.jrras.2026.102774 · W7225291641
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PLA2G2A drives macrophage pro-fibrotic polarization via the MAT2A/SAM-SCD1 axis in endometriosis, while small extracellular vesicles activate stromal cells through PPARγ signaling to establish a reciprocal paracrine feedback loop.

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Abstract

Background Endometriosis (EMS) is a persistent inflammatory condition defined by the presence of both immunomicroenvironmental disturbances and advancing fibrosis. However, little is currently known about how macrophages promote their own fibrosis through metabolic reprogramming. The objective of this research was to explore whether Phospholipase A2 Group IIA (PLA2G2A) drives macrophage pro-fibrotic polarization through the methionine cycle/Stearoyl-CoA desaturase 1 (SCD1) axis and establishes a positive feedback network with stromal cells in EMS. Methods Public transcriptomic data were analyzed for macrophage–stromal crosstalk. Functional assays conducted in vitro utilized macrophages derived from THP-1 and human endometrial stromal cells (hESCs), with pharmacological and genetic interventions to investigate the effects of the PLA2G2A/MAT2A/SAM-SCD1 axis on macrophage polarization. Meanwhile, small extracellular vesicle (sEV) isolation and conditioned medium transfer assays were employed to evaluate bidirectional communication between macrophages and stromal cells. Results Public transcriptomic datasets supported macrophage-to-stromal pro-fibrotic signaling but showed sparse PLA2G2A detection, weak PLA2G2A–SCD1 coupling, and incomplete support for a reciprocal feedback network. Notably, lipid-synthesis and pro-fibrotic programs were directionally inconsistent across cohorts, indicating a fragile, dataset-dependent signal; in contrast, GSE19834 conditioned-medium experiments consistently supported the macrophage-to-stromal direction. Functionally, PLA2G2A overexpression upregulated SCD1 and promoted M2-like polarization (Upregulated expression: Arg-1 and CD206; Down-regulated expression: iNOS and CD86) with enhanced TGF-β1/PDGF secretion; MAT2A inhibition abrogated these effects, SAM supplementation partially restored them, and SCD1 knockdown markedly attenuated PLA2G2A-driven polarization. Macrophage-derived sEV activated stromal cells through PPARγ signaling (Upregulated expression: α-SMA, Col-I, CD36, FABP4), which was attenuated by PPARγ inhibition; conditioned medium from activated stromal cells feedback-reinforced macrophage pro-fibrotic polarization. Conclusion PLA2G2A overexpression drives macrophage pro-fibrotic polarization, which requires the MAT2A/SAM axis and SCD1, and LR-PFM-derived sEV activate stromal cells through PPARγ signaling, potentially constituting a paracrine feedback mechanism. These findings provide new avenues for exploring the underlying mechanisms of EMS-associated fibrosis.

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