Targeting SOAT1 restores lipophagy and attenuates PHMG-induced pulmonary fibrosis.

Inhalational exposure to polyhexamethylene guanidine (PHMG), a common disinfectant, poses major public health risks, causing severe and often fatal pulmonary fibrosis with no specific treatment available. Our prior research has demonstrated that when C57BL/6J mice are exposed to PHMG via a whole-body exposure system equipped with an ultrasonic nebulizer (3 weeks of exposure followed by a 3-week recovery period), PHMG induces pulmonary fibrosis in the mice. A key pathological feature accompanies this process: the accumulation of foam cells derived from alveolar macrophages. However, the underlying molecular mechanism driving foam cell formation remains unclear. In this study, we identified sterol O-acyltransferase 1 (SOAT1) as a critical mediator of PHMG-induced lung injury for the first time-this role had not been recognized before. Using in vivo (PHMG-exposed mice) and in vitro (lipid-loaded macrophage) models, we found PHMG exposure significantly upregulates SOAT1 in alveolar macrophages, directly disrupting cholesterol homeostasis and blocking lipophagy. This leads to excessive cholesteryl ester accumulation, promoting pro-fibrotic foam cell formation. These foam cells then secrete factors like TGF-β to activate fibroblasts. Our results confirm SOAT1 as a novel target for PHMG-induced pulmonary fibrosis. Notably, avasimibe, a selective SOAT1 inhibitor with confirmed safety, exerts multiple therapeutic effects in preclinical models. Given the growing global PHMG market and persistent human exposure risks, inhibiting SOAT1 is a feasible "drug repurposing" strategy. Additionally, SOAT1-mediated lipid dysregulation may offer a new therapeutic direction for other lipid metabolism-related fibrotic lung diseases.