TY  - JOUR
T1  - Metabolic Dysfunction-associated Steatotic Liver Disease Diminishes the Efficacy of miR-125b-5p-engineered MSC Therapy for Hepatocellular Carcinoma via HK2 Upregulation: A Multimodal Theranostic Study 
AU  - Shen, Lishan
AU  - Luo, Xiaowen
AU  - Su, Xiaorui
AU  - Zhou, Xiang
AU  - Zou, Fengyun
AU  - Zhong, Shuangshuang
AU  - Deng, Yayin
AU  - Yin, Boya
AU  - Yao, Zhicheng
AU  - Guo, Ruomi
JF  - Journal of Clinical and Translational Hepatology
VL  - 
IS  - 000
SN  - 2310-8819
SP  - 
EP  - 
Y1  - 2026-05-11
DO  - 10.14218/JCTH.2025.00709
UR  - https://www.xiahepublishing.com/2310-8819/JCTH-2025-00709
AB  - 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 an 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 magnetic resonance imaging (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
Multigene-modified MSCs enable effective, MRI-monitored HCC therapy. MASLD diminishes the efficacy of miR-125b-5p through HK2 upregulation. These findings establish a multimodal theranostic framework for HCC and provide mechanistic insights into MASLD-associated therapeutic resistance.