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

ABSTRACT: Background: The molecular mechanism of metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma (HCC) remains poorly understood, and effective treatments are lacking. This study aimed to elucidate translational repurposing of Resmetirom and the underlying mechanistic basis for MASH-associated hepatocarcinogenesis and therapeutic actions of Resmetirom. Approach and Results: Repurposing Resmetirom, a clinically approved thyroid hormone receptor-beta agonist, yielded notable tumor-suppressive effects in MASH-HCC preclinical models. Next. we employed a Western diet combined with CCl₄-induced MASH-HCC murine model, complemented by single-cell RNA sequencing (scRNA-seq) analyses of liver and tumor tissues to characterize the specific cellular interactions within the tumor microenvironment of MASH-HCC. Analysis of 134,760 single-cell transcriptomes revealed that hepatic stellate cells (HSCs) and dysplastic hepatocytes (dys-Heps) exhibit prominent cell-cell communication within the tumor milieu. Notably, midkine (MDK) was markedly upregulated in activated HSCs and dys-Heps, where it facilitated M2-like macrophage polarization through interaction with the receptor LRP1 at multiple stages from MASH development to fibrosis and eventual HCC formation. Treatment with Resmetirom led to significant tumor suppression, concomitant reductions in hepatic steatosis, and decreased MDK expression, but increased Thrb levels. Clinically, elevated MDK expression in human HCC samples correlated with markedly shorter relapse-free survival among patients with non-viral, non-alcohol-related HCC. Functional experiments demonstrated that silencing LRP1 in macrophages abolished MDK-driven M2 polarization and elevated secretion of cytotoxic cytokines. Furthermore, LRP1-positive macrophages promoted cytotoxic T cell exhaustion and auto-aggression via the CXCL16-CXCR6 axis. Pharmacological combination of Resmetirom and iMDK showed synergistic suppression of tumorigenesis in vivo. Conclusions: Therapeutic repurposing of Resmetirom, mechanistically via targeting MDK/LRP1 signaling axis, presents a promising strategy for mitigating MASH-associated HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE317301 | GEO | 2026/08/26

REPOSITORIES: GEO