Liver cancer-derived exosomal PTK6 induces the secretion of pulmonary CHI3L1 to facilitate lung metastatic niche formation.

Pulmonary metastasis represents the most frequent site of distant dissemination in hepatocellular carcinoma (HCC). Elevated levels of Chitinase-3-like protein 1 (CHI3L1) in HCC patients are specifically associated with pulmonary metastasis, compared to metastasis to other sites or the absence of metastasis. HCC-derived exosomes, enriched in protein tyrosine kinase 6 (PTK6), induced CHI3L1 secretion in pulmonary epithelial cells via PTK6-mediated STAT3 phosphorylation (p-STAT3), thereby promoting angiogenesis and facilitating the establishment of a lung pre-metastatic niche. Elevated CHI3L1 enhanced HCC cell migration and angiogenesis, facilitating pulmonary metastatic niche formation. Targeting CHI3L1 with neutralizing antibodies or AAV2-shChi3l1 knockdown in pulmonary cells significantly reduced lung metastasis in vivo. Furthermore, Bortezomib suppressed CHI3L1 secretion in vitro and in vivo, inhibiting HCC lung metastasis. This study establishes CHI3L1 as a specific biomarker and a therapeutic target for HCC pulmonary metastasis.