Sharafi Faezeh, Rismani Elham, Rhmanian Mohamad, Khosravi Arezoo, Zarrabi Ali, Vosough Massoud
Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Molecular Medicine Department, Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran.
Mol Cell Biochem. 2025 Aug 30. doi: 10.1007/s11010-025-05377-x.
Globally, liver cancer is reported to be the third leading cause of cancer-related mortality. The most common type of these cancers is hepatocellular carcinoma (HCC). Current preventive strategies, including lifestyle modifications, antiviral therapies, and surveillance, are limited in their effectiveness. Mitochondria play critical roles in regulating cellular metabolism, oxidative stress, and apoptosis. Mitochondrial dysfunction can accelerate HCC progression, particularly in patients with liver diseases such as metabolic-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this review, we discuss the mechanisms of mitochondrial dysfunction in HCC from a molecular point of view, including oxidative stress, mitophagy dysregulation, mitochondrial dynamics dysregulation, and mitochondrial DNA (mtDNA)-mediated dysregulation of innate immune responses. Additionally, we explore molecular-targeted therapies aimed at restoring mitochondrial function. Critical approaches include targeting reactive oxygen species pathways through agents such as iridium (III) complexes and Mito Rh S, which induce cancer cell death through apoptosis and ferroptosis. Other compounds, including dehydrocrenatidine, enhance oxidative phosphorylation and promote apoptosis. Inhibitors of dynamin-related protein 1 (Drp1) target mitochondrial fission to reduce tumor growth. Furthermore, mitophagy modulators, such as SIRT1 activators, improve mitochondrial quality control, minimize the negative effects of oxidative stress, and reduce cancer development. Clinical trials are ongoing for the mitochondrial enzyme-targeting agents CPI-613 and Gamitrinib, a heat shock protein-targeting agent, which have hence shown great promise for these therapies. With further investigation, mitochondrial-targeted interventions could be promising for preventing or reducing HCC incidence and recurrence, increasing long-term survival, and improving the quality of life of patients with advanced-stage disease.
据全球报告，肝癌是癌症相关死亡的第三大主要原因。这些癌症中最常见的类型是肝细胞癌（HCC）。目前的预防策略，包括生活方式改变、抗病毒治疗和监测，其效果有限。线粒体在调节细胞代谢、氧化应激和细胞凋亡中起关键作用。线粒体功能障碍可加速HCC进展，特别是在患有代谢相关脂肪性肝病（MAFLD）和代谢功能障碍相关脂肪性肝炎（MASH）等肝脏疾病的患者中。在本综述中，我们从分子角度讨论HCC中线粒体功能障碍的机制，包括氧化应激、线粒体自噬失调、线粒体动力学失调以及线粒体DNA（mtDNA）介导的先天免疫反应失调。此外，我们探索旨在恢复线粒体功能的分子靶向治疗。关键方法包括通过铱（III）配合物和Mito Rh S等药物靶向活性氧途径，这些药物通过凋亡和铁死亡诱导癌细胞死亡。其他化合物，包括脱氢马钱子碱，可增强氧化磷酸化并促进凋亡。动力蛋白相关蛋白1（Drp1）抑制剂靶向线粒体分裂以减少肿瘤生长。此外，线粒体自噬调节剂，如SIRT1激活剂，可改善线粒体质量控制，将氧化应激的负面影响降至最低，并减少癌症发展。针对线粒体酶靶向药物CPI-613和热休克蛋白靶向药物Gamitrinib的临床试验正在进行，因此这些疗法显示出巨大的前景。随着进一步研究，线粒体靶向干预措施有望预防或降低HCC的发病率和复发率，提高长期生存率，并改善晚期疾病患者的生活质量。
