Fibroblast collagen synthesis is a hallmark of the pathogenesis and progression of pulmonary fibrosis (PF). However, the factors that trigger the abnormal activation of fibroblasts in PF are still not well understood. Using proteomics and single-cell sequencing dataset screening, extra accumulation of Cathepsin K (CTSK) is detected in the periphery as well as in fibroblasts in the lungs of PF mouse models. Addition of recombinant CTSK (rCTSK) aggravates collagen accumulation and PF progression in bleomycin-induced PF mice. Mechanically, CTSK underwent endocytosis through interaction with sorting nexin 9 (SNX9), which is engaged in TGF-β1 induced SMAD3 activation for downstream glutaminase 1 (GLS1) upregulation and glutamine enrichment. In turn, extra glutamine increases collagen synthesis in fibroblasts. More significantly, serum CTSK levels positively correlated with glutamine levels and poor prognosis in patients with PF. Thus, the results identify CTSK as a novel regulator of fibroblast activation that remodels glutamine metabolism and promotes collagen synthesis during PF pathogenesis. The correlation between peripheral CTSK and glutamine levels implies its future feasibility in the prediction and prevention of PF progression.
Keywords: CTSK; SNX9; collagen synthesis; glutamine metabolism; pulmonary fibrosis.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.