Metabolic dysfunction-associated steatotic liver disease diminishes the efficacy of miR-125b-5p-engineered MSC therapy for hepatocellular carcinoma via HK2 upregulation

Background and Aims

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for effective therapies. Although miR-125b-5p shows therapeutic potential, its efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC and the underlying mechanisms remain unclear. In this study, we aimed to develop a magnetic resonance imaging (MRI)-trackable miR-125b-5p-engineered MSC platform for HCC therapy and to determine whether MASLD attenuates its antitumor efficacy through metabolic reprogramming.

Methods

Bone marrow mesenchymal stem cells (MSCs) were genetically engineered to coexpress miR-125b-5p (a therapeutic gene) and ferritin heavy chain (Fth; a MRI reporter gene), enabling sustained delivery and real-time tracking. Orthotopic HCC models with or without MASLD were established to evaluate therapeutic outcomes. In vivo MRI, histological analyses, and bioinformatics approaches were used to assess efficacy and mechanisms.

Results

Transplantation of miR-125b-5p-Fth-MSCs significantly suppressed HCC growth in vivo over an extended period. However, MASLD attenuated this therapeutic effect. Mechanistically, miR-125b-5p directly targeted hexokinase 2 (HK2), inhibiting HCC proliferation and migration through suppression of the PI3K/AKT/mTOR pathway. Fatty acid-induced lipotoxicity upregulated HK2 expression and counteracted the antitumor effects of miR-125b-5p.

Conclusions

This study demonstrated that miR-125b-5p-engineered MSCs exerted potent antitumor effects against HCC through HK2 downregulation and PI3K/AKT/mTOR pathway inhibition, while Fth enabled noninvasive MRI tracking. Importantly, we identified MASLD-associated metabolic dysregulation as a resistance mechanism characterized by HK2 upregulation and PI3K/AKT/mTOR pathway reactivation. These findings have important clinical implications. First, HCC patients with underlying MASLD may require stratified therapeutic approaches rather than being managed identically to other HCC subtypes. Second, combination strategies targeting HK2 or lipid metabolism may be needed to overcome resistance. Finally, quantitative MRI parameters may serve as early biomarkers of treatment response and could facilitate individualized treatment adaptation. Overall, this study provides a foundation for the rational design of MSC-based theranostic strategies for HCC while emphasizing the importance of host metabolic status in therapeutic design and response assessment.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2025-00709

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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