Wu Ming-Feng, Peng Xi, Zhang Ming-Chang, Guo Huan, Xie Hua-Tao
Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Free Radic Biol Med. 2025 Feb 16;228:173-182. doi: 10.1016/j.freeradbiomed.2024.12.050. Epub 2025 Jan 4.
Cell death under stress conditions like hypoxia, involves multiple interconnected pathways. In this study, a stable dihydroorotate dehydrogenase (DHODH) knockdown human corneal epithelial cell line was established to explore the regulation of hypoxic cell death, which was mitigated by various cell death inhibitors, particularly by a lipid peroxyl radical scavenger liproxstatin-1 (Lip-1), suggesting that hypoxic cell death involves crosstalk of ferroptosis and PANoptosis. We discovered that both DHODH and Glutathione peroxidase 4 (GPX4) protected cells from hypoxic death by inhibiting lipid peroxidation, mitochondrial reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. However, upregulation of DHODH suppressed GPX4 upstream, exhibiting a trade-off in the expression levels between DHODH and GPX4 under hypoxia, with DHODH exerting a more decisive impact on cell survival. DHODH knockdown under hypoxia did not significantly alter lipid peroxidation levels, demonstrating the balance between DHODH and GPX4 expression finely regulated cellular ferroptosis homeostasis. This study highlights the complex interplay between ferroptosis and PANoptosis in hypoxic cell death, particularly the dual role of DHODH in regulating both pathways. DHODH is not merely maintaining the quantity of mitochondria but is promoting the selection of mitochondria favorable to cell survival. These findings not only deepen our understanding of cell death but also suggest potential therapeutic strategies for diseases involving oxidative stress and mitochondrial dysfunction.
在缺氧等应激条件下的细胞死亡涉及多个相互关联的途径。在本研究中，建立了一种稳定的二氢乳清酸脱氢酶（DHODH）敲低的人角膜上皮细胞系，以探索缺氧细胞死亡的调控机制。各种细胞死亡抑制剂可减轻这种死亡，特别是脂质过氧自由基清除剂脂氧素-1（Lip-1），这表明缺氧细胞死亡涉及铁死亡和PANoptosis的相互作用。我们发现，DHODH和谷胱甘肽过氧化物酶4（GPX4）都通过抑制脂质过氧化、线粒体活性氧（ROS）并维持线粒体膜电位来保护细胞免受缺氧死亡。然而，DHODH的上调在GPX4上游起抑制作用，在缺氧条件下DHODH和GPX4的表达水平呈现出一种权衡，其中DHODH对细胞存活发挥更具决定性的影响。缺氧条件下DHODH敲低并未显著改变脂质过氧化水平，这表明DHODH和GPX4表达之间的平衡精细地调节了细胞铁死亡稳态。本研究突出了铁死亡和PANoptosis在缺氧细胞死亡中的复杂相互作用，特别是DHODH在调节这两种途径中的双重作用。DHODH不仅维持线粒体的数量，还促进对细胞存活有利的线粒体的选择。这些发现不仅加深了我们对细胞死亡的理解，还为涉及氧化应激和线粒体功能障碍的疾病提出了潜在的治疗策略。
