促存活 BCL-2 蛋白通过抑制促凋亡蛋白 BAX 和 BAK 来防止内在凋亡（线粒体依赖性途径）的启动，而仅 BH3 蛋白则通过阻断促存活 BCL-2 蛋白来促进细胞凋亡。这种微妙平衡的破坏有助于癌细胞的存活和化疗耐药性。癌症治疗的最新进展涉及称为 BH3 模拟物的新一代药物，它们是旨在模拟 BH3 蛋白作用的小分子。在接受这些药物治疗的血液肿瘤和实体瘤患者中观察到了有希望的效果。然而，据报道，线粒体依赖性的 BH3 模拟物耐药性迅速出现。这种抵抗涉及线粒体呼吸增加、线粒体自噬改变以及线粒体嵴更高更紧。相反，异柠檬酸脱氢酶 1 和 2 的突变催化 R-2-羟基戊二酸的产生，从而提高对 Venetoclax 的敏感性。这一证据强调了对 BH3 模拟物敏感和耐药癌细胞中基于生物能量学的适应性反应进行全面研究的紧迫性。正在进行的临床试验正在评估 BH3 模拟物与标准化疗药物的组合。在本文中，我们讨论了线粒体生物能量学在 BH3 模拟物反应中的作用，并通过代谢靶向策略探索潜在的治疗机会。版权所有 © 2024。由 Elsevier B.V. 出版。

Pro-survival BCL-2 proteins prevent the initiation of intrinsic apoptosis (mitochondria-dependent pathway) by inhibiting the pro-apoptotic proteins BAX and BAK, while BH3-only proteins promote apoptosis by blocking pro-survival BCL-2 proteins. Disruptions in this delicate balance contribute to cancer cell survival and chemoresistance. Recent advances in cancer therapeutics involve a new generation of drugs known as BH3-mimetics, which are small molecules designed to mimic the action of BH3-only proteins. Promising effects have been observed in patients with hematological and solid tumors undergoing treatment with these agents. However, the rapid emergence of mitochondria-dependent resistance to BH3-mimetics has been reported. This resistance involves increased mitochondrial respiration, altered mitophagy, and mitochondria with higher and tighter cristae. Conversely, mutations in isocitrate dehydrogenase 1 and 2, catalyzing R-2-hydroxyglutarate production, promote sensitivity to Venetoclax. This evidence underscores the urgency for comprehensive studies on bioenergetics-based adaptive responses in both BH3 mimetics-sensitive and -resistant cancer cells. Ongoing clinical trials are evaluating BH3-mimetics in combination with standard chemotherapeutics. In this article, we discuss the role of mitochondrial bioenergetics in response to BH3-mimetics and explore potential therapeutic opportunities through metabolism-targeting strategies.Copyright © 2024. Published by Elsevier B.V.