Cigarette smoke-induced glycerophospholipid DLPC promotes macrophage ferroptosis through the USP7/GPX4 regulatory axis in chronic obstructive pulmonary disease.

Abstract

Chronic obstructive pulmonary disease (COPD), a smoking-associated chronic inflammatory disorder, involves macrophage-mediated inflammation and cell death, yet the mechanisms linking cigarette smoke (CS) to macrophage ferroptosis remain unclear. Through integrated transcriptomic and metabolomic analyses of CS-exposed macrophages, we identified activation of the ferroptosis pathway accompanied by dysregulated glycerophospholipid metabolism. Notably, phosphatidylcholine species enriched in polyunsaturated fatty acids (PUFA-PC), particularly 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), were markedly elevated. Functional studies revealed that DLPC exacerbated lipid peroxidation and triggered ferroptosis in macrophages. Mechanistically, DLPC downregulated the deubiquitinase ubiquitin-specific peptidase 7 (USP7), which normally stabilizes glutathione peroxidase 4 (GPX4) through TRAF/CAT domain-mediated binding and deubiquitination activity. This suppression accelerated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, CS upregulated glycerol-3-phosphate acyltransferase 3 (GPAT3), whose genetic ablation diminished PUFA-PC (including DLPC) synthesis, attenuated lipid reactive oxygen species (ROS) accumulation, and inhibited ferroptosis in CS-stimulated macrophages. In vivo, adeno-associated virus-mediated GPAT3 knockdown in murine lung tissues mitigated ROS production, ferroptosis, and emphysema in an experimental emphysema murine model. Collectively, our findings delineate a CS-GPAT3-DLPC axis that drives macrophage ferroptosis via USP7/GPX4 dysregulation, offering novel mechanistic insights into COPD pathogenesis and identifying DLPC and GPAT3 as potential therapeutic targets.