Endotrophin and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Crosstalk and Facilitates Malignant Progression in Hepatocellular Carcinoma

Endotrophin (ETP) is a cleavage fragment of collagen VI α3 (COL6A3) that functions as a potent fibrotic and pro-tumorigenic factor. ETP is a diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC), continuously increasing throughout tumor development and promoting HCC progression. Elucidation of the underlying molecular mechanisms by which ETP exerts pro-tumorigenic effects in the liver could uncover potential therapeutic strategies. Using peroxidase-catalyzed proximity labeling, we identified CD44 as an ETP receptor. ETP binding to CD44 activated STAT3 signaling, promoting epithelial-mesenchymal transition (EMT), proliferation, and sorafenib resistance. Hepatic stellate cell-derived ETP targeted pericentral CD44+ tumor cells, inducing COL6A3 expression and sustaining ETP production via a STAT3-dependent feedback loop. Disruption of this axis by CD44 knockout, STAT3 inhibition, or CD44-binding-deficient ETP mutants suppressed malignant phenotypes in vitro. In metabolic dysfunction-associated HCC induced by diethylnitrosamine (DEN) plus high-fat diet (HFD), dual knockout of Col6a3 and Cd44 in mice markedly reduced tumor burden, restored sorafenib sensitivity, and attenuated EMT, fibrosis, and steatotic-fibrotic niche formation. These findings establish the ETP-CD44-STAT3 axis as a driver of tumor-stroma crosstalk linking fibro-inflammation to malignancy, highlighting it as a therapeutic target in obesity-associated liver cancer.