Targeting CXCR4–JNK/c-Jun–CTSB Signaling Axis Attenuates Silicosis Fibrosis in Mice

Silicosis is a severe occupational lung disease characterized by progressive and irreversible pulmonary fibrosis. CXCR4 (C-X-C chemokine receptor type 4) has been implicated in the pathogenesis of silicosis, yet the specific molecular mechanism through which CXCR4 signaling promotes fibrotic progression remain unclear. In this study, we systematically investigated the role of CXCR4 in silica-induced lung inflammation and fibrosis using pharmacological inhibition with AMD3100 and conditional Cxcr4 knockout mouse models, supported by complementary in vitro mechanistic studies. Silica exposure significantly upregulated CXCR4 expression in the lungs, which was accompanied by activation of the JNK/c-Jun pathway and enhanced transcription of cathepsin B (CTSB). Both AMD3100 treatment and genetic deletion of Cxcr4 markedly reduced inflammatory cell infiltration, collagen deposition, and lung function impairment, while also suppressing the expression of CTSB, TGF-β1, α-SMA, and fibronectin. Mechanistically, CXCR4 activation promoted JNK-dependent phosphorylation of c-Jun, enabling c-Jun to bind directly to the Ctsb promoter and drive its transcription. The subsequent increase in CTSB levels facilitated TGF-β1 activation, thereby amplifying downstream profibrotic signaling. Notably, CTSB was predominantly expressed in macrophages, where it co-localized with C1QC and was positively regulated by CXCR4 signaling. Taken together, our findings reveal a previously unrecognized CXCR4–JNK/c-Jun–CTSB signaling axis in macrophages that drives silica-induced pulmonary fibrosis, highlighting CXCR4 as a promising therapeutic target for silicosis.