Repurposing resmetirom suppresses MASH-associated hepatocellular carcinoma, with mechanistic implications of MDK/LRP1-mediated metabolic reprogramming and immunosuppression

Background & Aims: The mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma (HCC) are poorly understood, and effective treatments are lacking. This study explored the translational potential of Resmetirom, a clinically approved thyroid hormone receptor-beta (Thrb) agonist and investigated the mechanistic basis of MASH-associated hepatocarcinogenesis. Approach & Results: Repurposing Resmetirom for MASH-HCC treatment demonstrated significant tumor-suppressive effects across multiple preclinical models. To further investigate its mechanisms, we employed a Western diet plus CCl₄-induced murine MASH-HCC model, complemented by single-cell RNA sequencing (scRNA-seq) analyses of liver and tumor tissues. These analyses revealed active cell-cell communication within the tumor microenvironment, particularly involving hepatic stellate cells (HSCs) and dysplastic hepatocytes (dys-Heps). These cells showed marked upregulation of midkine (MDK), which in human HCC correlated with shorter relapse-free survival, specifically in non-viral, non-alcohol-related cases. In mouse models, MDK facilitated M2-like macrophage polarization via interaction with the receptor LRP1, contributing to disease progression from MASH to fibrosis and eventual HCC. Silencing LRP1 in macrophages abolished MDK-driven M2 polarization and increased cytotoxic cytokine secretion, while LRP1-positive macrophages contributed to T cell exhaustion through the CXCL16-CXCR6 axis. MDK expression negatively correlated with Thrb and lipolytic genes, but positively with lipogenesis genes. Resmetirom treatment not only significantly suppressed tumor growth and reduced steatosis but also decreased MDK expression and increased Thrb levels. Combining Resmetirom and an MDK inhibitor (iMDK) synergistically suppressed tumorigenesis in vivo. Conclusions: Targeting the MDK/LRP1 axis with Resmetirom offers a promising therapeutic strategy for MASH-associated HCC, addressing both metabolic dysfunction and tumor progression.