肝癌线粒体功能障碍:从代谢到靶向治疗。

IF 3.7 2区 生物学 Q3 CELL BIOLOGY
Faezeh Sharafi, Elham Rismani, Mohamad Rhmanian, Arezoo Khosravi, Ali Zarrabi, Massoud Vosough
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引用次数: 0

摘要

据报道,在全球范围内,肝癌是癌症相关死亡的第三大原因。这些癌症最常见的类型是肝细胞癌(HCC)。目前的预防策略,包括改变生活方式、抗病毒治疗和监测,其有效性有限。线粒体在调节细胞代谢、氧化应激和细胞凋亡中起着重要作用。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。在这篇综述中,我们从分子角度讨论了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、线粒体动力学失调和线粒体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。关键的方法包括通过铱(III)复合物和Mito Rh S等药物靶向活性氧途径,它们通过细胞凋亡和铁凋亡诱导癌细胞死亡。其他化合物,包括脱氢骨碱,增强氧化磷酸化和促进细胞凋亡。动力蛋白相关蛋白1 (Drp1)抑制剂靶向线粒体裂变以减少肿瘤生长。此外,线粒体自噬调节剂,如SIRT1激活剂,改善线粒体质量控制,最大限度地减少氧化应激的负面影响,并减少癌症的发展。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中,因此在这些治疗中显示出很大的希望。随着进一步的研究,线粒体靶向干预有望预防或减少HCC的发病率和复发,增加长期生存率,并改善晚期疾病患者的生活质量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies.

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.

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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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