Recently, the involvement of CTS family members in lung injury‐induced fibrosis has been addressed yet with controversial conclusions.[38] Herein we have shown that CTSK was most abundantly expressed in the fibroblasts from PF mouse models as well as in human lung samples with PF, which is similar to silica‐induce PF mice.[21] Moreover, we have elucidated that CTSK could serve as an extracellular ligand to interact with SNX9 followed by endocytosis and activation of TGF‐β1‐SMAD3 signaling for downstream collagen synthesis partially depending on glutamine metabolism. This evidence concerns the gene TTR and pemphigus foliaceus.