Liver-lung communication of cirrhosis-derived CHI3L1 drives hepatocellular carcinoma metastasis after liver transplantation

Background: Lung metastasis is the most common form of extrahepatic recurrence for hepatocellular carcinoma (HCC) after liver transplantation. However, the mechanisms underlying the liver-lung communication in this process under liver cirrhosis remain elusive.
Methods: Peritumoral tissue cirrhosis severity assessed by Masson staining was correlated with serum CHI3L1 levels and prognosis in HCC patients underwent liver transplantation (n=178). CHI3L1 expression was localized in paired tumor and peritumoral tissues via Immunohistochemistry. Mouse models of CCl4-induced liver fibrosis combined with tail vein or intrasplenic HCC cell injection were used to study lung metastasis. CHI3L1 knockout mice and recombinant CHI3L1 protein administration were employed to assess metastatic progression. Single-cell RNA sequencing of lung tissues, coupled with in vitro fibroblast and T-cell functional assays, and galectin-3 inhibition experiments, elucidated the underlying mechanisms.
Results: Masson staining positive aera > 30% of peritumoral tissue predicted poor survival and high lung metastasis rate in HCC patients underwent liver transplantation. Elevated serum CHI3L1 independently correlated with inferior outcomes and cirrhosis severity (R=0.280, P=0.003). CHI3L1 expression of peritumoral tissue was strongly correlated with circulating levels (R=0.520, P<0.001), identifying cirrhotic tissue as the primary source. In mice, CCl4-induced liver fibrosis elevated serum CHI3L1 and increased lung metastases (P<0.05). CHI3L1 knockout mice exhibited reduced lung metastases, while rCHI3L1 protein promoted them. Single-cell sequencing revealed CHI3L1 activating fibroblasts and implicated the galectin pathway in fibroblast-T cell interactions. CHI3L1 activated fibroblasts exhibiting increased FAP, COL1A1, and galectin-3 expression via JAK2-STAT3 signaling pathway, and suppressed T-cell cytotoxicity. Galectin-3 inhibition reversed fibroblast activation and restored T-cell function, suggesting that Galectin-3 as a potential therapeutic target for preventing HCC lung metastasis.
Conclusion: Cirrhosis-derived CHI3L1 promotes HCC lung metastasis after liver transplantation by activating lung fibroblasts via JAK2-STAT3 signaling pathway, increasing galectin-3 expression, and subsequently impairing T-cell cytotoxicity. Targeting the CHI3L1-galectin-3 axis may offer a novel therapeutic strategy to mitigate metastasis for HCC patients underwent liver transplantation.