Research: Obesity Fuels Aggressive, Resistant Liver Cancer

Abstract

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.

A research team, affiliated with UNIST has made a significant discovery explaining why liver cancers associated with obesity and metabolic disorders tend to be more aggressive and less responsive to conventional treatments. The study reveals that a specific signaling pathway involving Endotrophin-a protein secreted during liver fibrosis-and the receptor protein CD44 promotes tumor malignancy and drug resistance.

Led by Professor Jiyoung Park of the Department of Biological Sciences at UNIST, the research team demonstrated, for the first time, how Endotrophin binds to CD44 on cancer cells, activating a cascade that accelerates tumor growth and invasion. This interaction also confers resistance to sorafenib, a common targeted therapy for liver cancer.

Liver cancer linked to obesity and metabolic dysfunction develops rapidly and poses significant treatment challenges due to its aggressive nature and poor response to existing drugs. Although elevated Endotrophin levels have been observed in patients with liver cancer, the precise molecular mechanisms remained unclear until now.

The team found that in obese liver tissue, excess Endotrophin interacts with CD44 on hepatocellular carcinoma (HCC) cells, triggering the STAT3 signaling pathway. This activation results in rapid tumor proliferation and increased invasive behavior.

Figure 1. Schematic model of the ETP-CD44-STAT3 axis driving metabolic dysfunction1047 associated HCC progression and chemoresistance.

Animal studies validated these findings: mice treated with inhibitors targeting both Endotrophin and CD44 exhibited markedly reduced tumor formation and size. Importantly, blocking this pathway also restored sensitivity to sorafenib and alleviated liver fibrosis and inflammation.

Professor Park explained, "Our research shows that the interaction between Endotrophin and CD44 is a key driver of liver cancer progression in obesity-related cases. Developing drugs to disrupt this interaction could weaken tumor aggressiveness and help overcome resistance to current therapies."

The study was led by Dr. Woobeen Jo from the Department of Biological Sciences at UNIST, and published online in Cancer Research-a leading journal of the American Association for Cancer Research (AACR)-on February 11, 2026.

This research was supported through the Bio-Medical Technology Development Project, the Basic Science Research Program, and the Mid-Career Researcher Program, funded by the National Research Foundation of Korea (NRF) by the Ministry of Science and ICT (MSIT).

Journal Reference

Woobeen Jo, Chanho Park, Min Kim et al., "Endotrophin and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Crosstalk and Facilitates Malignant Progression in Hepatocellular Carcinoma," Cancer Res., (2026).