Liver X receptor agonist RGX-104 attenuates PHMG-induced pulmonary fibrosis by restoring autophagy–lysosome fusion and suppressing macrophage foaming

Polyhexamethylene guanidine (PHMG) has broad-spectrum antibacterial and disinfectant properties and is widely used as a component in humidifier disinfectants. Exposure to PHMG aerosols is known to induce pulmonary fibrosis, and our previous study showed that foamy transformation in alveolar macrophages contributes to PHMG-induced pulmonary fibrosis. However, the underlying mechanisms are not fully understood. This study primarily focused on elucidating the mechanisms by which PHMG induces the formation of foamy macrophages. C57BL/6 J mice were exposed to PHMG aerosol for six weeks. PHMG induced pulmonary fibrosis with foamy macrophage formation, which was associated with lipid metabolism disorders and autophagy dysfunction in alveolar macrophages. In vitro experiments further confirmed that PHMG inhibited both autophagy-lysosome fusion and the recruitment of lipid droplets to autophagosomes in alveolar macrophages, leading to autophagy dysfunction. Inhibition of TFEB nuclear translocation was identified as a key regulator of PHMG-induced autophagy-lysosome fusion defects. In this study, we revealed the molecular mechanism underlying autophagy-lysosome fusion defects that mediate foamy macrophage formation, which plays an important role in PHMG-induced pulmonary fibrosis. RGX-104 facilitated TFEB translocation into the nucleus, promoted the fusion of autophagosomes with lysosomes, and ameliorated foaming and fibrosis. Enhancing autophagy-lysosome fusion may represent a critical therapeutic target to prevent PHMG-induced fibrosis and alleviate symptoms in affected patients.