AMD3100 inhibition of CXCR4 attenuates silica-induced pulmonary fibrosis through suppression of HIF-1α/SREBP1-mediated lipid metabolic reprogramming

Inhalation of crystalline silica induces persistent pulmonary inflammation, fibroblast activation and excessive extracellular matrix deposition, ultimately leading to progressive pulmonary fibrosis and irreversible loss of lung function. Although previous studies have shown that the CXCR4 antagonist AMD3100 can attenuate the severity of fibrosis, the underlying molecular mechanisms remain incompletely understood. Emerging evidence indicates that lipid metabolic reprogramming is a critical process in the pathogenesis of pulmonary fibrotic diseases. In this study, we established a murine model of silicosis and administered the CXCR4 inhibitor AMD3100 as a pharmacological intervention. We additionally generated Macrophage-specific Knockout of CXCR4 mice and integrated transcriptomic and metabolomic analyses to investigate the underlying mechanisms. We found that both pharmacological inhibition and macrophage-specific deletion of CXCR4 markedly attenuated silica-induced pulmonary fibrosis, accompanied by suppression of CXCR4–HIF-1α–SREBP1 axis-mediated lipid metabolic reprogramming. These effects were supported by reduced expression of lipid metabolism-associated proteins, including FAS, ACC1, ACLY and SCD1, as well as inflammatory and fibrotic markers, including TNF-α, α-SMA, fibronectin, TGF-β1 and COL1A1. Furthermore, inhibition of SREBP1 with fatostatin attenuated silica-induced activation of lipogenic pathways and TGF-β1 expression in macrophages, supporting a functional role for SREBP1-dependent lipid metabolic reprogramming in silica-induced fibrotic responses. Collectively, our findings identify CXCR4/HIF-1α/SREBP1-mediated lipid metabolic reprogramming as a central mechanism underlying silica-induced pulmonary fibrosis and suggest that pharmacological targeting of metabolic dysregulation with AMD3100 may represent a promising therapeutic strategy for silicosis.