The Role of Mitochondrial Dysfunction in Hepatocellular Carcinoma: From Pathogenesis and Drug Resistance to Targeted Therapeutic Strategies

Siyu Zhao,1 Qian Liu,1 Jing Li,1 Shilei Zhang,1 Shuo Wan,1– 3 Yuan Yang,1– 3 Feng Jin,4,5 Biguang Tuo,1– 3,6 Hai Jin1– 3,61Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, People’s Republic of China; 2Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, People’s Republic of China; 3Guizhou Clinical Research Center for Digestive Diseases, Zunyi, Guizhou, 563003, People’s Republic of China; 4Key Laboratory of Basic Pharmacology of the Ministry of Education of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 5Joint Laboratory of International Cooperation of the Ministry of Education of Characteristic Ethnic Medicine, Zunyi, Guizhou, 563000, People’s Republic of China; 6Key Laboratory for Cancer Prevention and Treatment of Guizhou Province, Zunyi, Guizhou, 563003, People’s Republic of ChinaCorrespondence: Hai Jin, Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan, Zunyi, Guizhou, 563003, People’s Republic of China, Email jinhai1115@aliyun.com Biguang Tuo, Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan, Zunyi, Guizhou, 563003, People’s Republic of China, Email tuobiguang@aliyun.comAbstract: Hepatocellular carcinoma (HCC) is characterized by high malignancy and widespread drug resistance at advanced stages, posing formidable challenges in clinical diagnosis and treatment. Mitochondrial dysfunction is a core driver of HCC initiation and drug resistance. However, how its plasticity dynamically regulates tumor growth under various conditions remains to be systematically elucidated. This review systematically delineates the critical roles of mitochondrial dysfunction in HCC pathogenesis, drug resistance, and targeted therapy. Regarding pathogenesis, we integrate four major pathways, namely aberrant oxidative phosphorylation (OXPHOS) coupled with mitochondrial DNA (mtDNA) mutations, glutamine metabolic reprogramming, oxidative stress imbalance, and dysregulated ferroptosis, to elaborate the molecular basis driving HCC malignant progression. In terms of drug resistance mechanisms, mitochondrial plasticity is highlighted as a central adaptive hub that synergistically promotes resistance through multifaceted mechanisms, including remodeling of the tumor immune microenvironment, dynamic regulation of OXPHOS levels, and modulation of ferroptosis sensitivity. With respect to therapeutic strategies, we summarize the current major intervention directions, encompassing ROS/OXPHOS modulators, inhibitors targeting mitochondrial metabolic enzymes and transporters, ferroptosis inducers, as well as nanodelivery systems and combination therapies. Of note, the efficacy of these interventions often depends on the mitochondrial phenotypic state of the tumor; single-target approaches tend to yield limited long-term benefits, whereas combination regimens or dynamic adjustments based on mitochondrial plasticity status hold greater promise for clinical application. Collectively, this review consolidates the evidence positioning mitochondrial dysfunction as a convergence point linking HCC progression, drug resistance, and targeted therapy, and proposes that "targeting mitochondrial plasticity” may represent a novel direction for overcoming drug resistance and achieving precision therapy, thereby providing a theoretical reference for future basic research and clinical translation.Keywords: hepatocellular carcinoma, mitochondrial dysfunction, drug resistance, mitochondrial plasticity, targeted therapy