Pan Jing, Li Jiaheng, Zhang Qi, Huang Mofei, Wang Yian, You Ming
Center for Cancer Prevention, Dr. Mary and Ron Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, United States.
Front Immunol. 2025 Apr 15;16:1539808. doi: 10.3389/fimmu.2025.1539808. eCollection 2025.
Bezafibrate (BEZ) is a drug used to treat hypertriglyceridemia and its long-term use has been associated with reduced risk of cancer in patients with coronary artery disease. Recent studies uncovered that BEZ is a potent modulator of mitochondrial biogenesis through activation of PGC-1α/PPAR complexes, resulting in modulation of lipid metabolism and fatty acid oxidation. Mitochondria impact virtually all processes linked to oncogenesis, and disruption of normal mitochondrial bioenergetics and oxidative phosphorylation (OXPHOS) occurs early during oncogenesis to change the energy metabolism of cancer cells as well as various cells in the tumor microenvironment (TME). Therefore, we synthesized a BEZ analog (Mito-BEZ) that preferentially localizes to mitochondria, thereby enabling lower doses of Mito-BEZ than BEZ to achieve greater efficacy. Our studies demonstrate that Mito-BEZ is significantly more potent than BEZ at inhibiting LUAD cell growth and inhibiting lung tumorigenesis in preclinical mouse models. Mito-BEZ was also >200-fold more potent than BEZ at inhibiting both complex I and III in LUAD cells. Furthermore, Mito-BEZ suppresses oxidative metabolism in cancer cells while markedly upregulating mitochondrial function in effector CD8+ T cells, resulting in activation of a potent T cell immune response in the TME. Our results show that Mito-BEZ, with its favorable toxicity profile, exhibited a striking inhibitory effect on lung cancer progression and metastasis by targeting a fundamental difference in metabolic plasticity between cancer cells and effector T cells in the TME.
苯扎贝特（BEZ）是一种用于治疗高甘油三酯血症的药物，长期使用该药物与降低冠心病患者的癌症风险相关。最近的研究发现，BEZ是线粒体生物发生的有效调节剂，可通过激活PGC-1α/PPAR复合物来调节脂质代谢和脂肪酸氧化。线粒体几乎影响与肿瘤发生相关的所有过程，在肿瘤发生早期，正常线粒体生物能量学和氧化磷酸化（OXPHOS）就会受到破坏，从而改变癌细胞以及肿瘤微环境（TME）中各种细胞的能量代谢。因此，我们合成了一种优先定位于线粒体的BEZ类似物（Mito-BEZ），从而使Mito-BEZ比BEZ以更低的剂量就能达到更高的疗效。我们的研究表明，在临床前小鼠模型中，Mito-BEZ在抑制LUAD细胞生长和抑制肺肿瘤发生方面比BEZ显著更有效。Mito-BEZ在抑制LUAD细胞中的复合物I和III方面也比BEZ强200倍以上。此外，Mito-BEZ抑制癌细胞中的氧化代谢，同时显著上调效应CD8+T细胞中的线粒体功能，从而在TME中激活强大的T细胞免疫反应。我们的结果表明，Mito-BEZ具有良好的毒性特征，通过针对TME中癌细胞和效应T细胞之间代谢可塑性的根本差异，对肺癌进展和转移表现出显著的抑制作用。
