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

Abstract

Endotrophin (ETP), a cleavage fragment of COL6A3, is a potent fibrotic and pro tumorigenic factor, but its receptor and signaling mechanisms in hepatocellular carcinoma (HCC) are unknown. Using peroxidase-catalyzed proximity labeling, we identified CD44 as a novel ETP receptor. ETP binding to CD44 activated STAT3 signaling, promoting epithelial mesenchymal transition (EMT), proliferation, and sorafenib resistance. Hepatic stellate cellderived 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 diethylnitrosamine (DEN) plus high-fat diet (HFD)-induced metabolic dysfunction-associated HCC mice, Col6a3/Cd44 double knockout 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.