Endotrophin- and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Cross-talk 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 protumorigenic 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 protumorigenic 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 plus high-fat diet, 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 cross-talk linking fibroinflammation to malignancy, highlighting it as a therapeutic target in obesity-associated liver cancer. CD44 serves as a receptor for endotrophin to activate STAT3 and drive EMT, fibroinflammatory niche formation, and malignant progression in metabolic dysfunction-associated hepatocellular carcinoma, suggesting this axis could represent a therapeutic target.