Qiu Yun, Hüther Juliana A, Wank Bianca, Rath Antonia, Tykwe René, Aldrovandi Maceler, Henkelmann Bernhard, Mergner Julia, Nakamura Toshitaka, Laschat Sabine, Conrad Marcus, Stöhr Daniela, Rehm Markus
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
Institute of Organic Chemistry, University of Stuttgart, Stuttgart, Germany.
Cell Death Differ. 2025 Apr 29. doi: 10.1038/s41418-025-01514-7.
Ferroptosis and apoptosis are widely considered to be independent cell death modalities. Ferroptotic cell death is a consequence of insufficient radical detoxification and progressive lipid peroxidation, which is counteracted by glutathione peroxidase-4 (GPX4). Apoptotic cell death can be triggered by a wide variety of stresses, including oxygen radicals, and can be suppressed by anti-apoptotic members of the BCL-2 protein family. Mitochondria are the main interaction site of BCL-2 family members and likewise a major source of oxygen radical stress. We therefore studied if ferroptosis and apoptosis might intersect and possibly interfere with one another. Indeed, cells dying from impaired GPX4 activity displayed hallmarks of both ferroptotic and apoptotic cell death, with the latter including (transient) membrane blebbing, submaximal cytochrome-c release and caspase activation. Targeting BCL-2, MCL-1 or BCL-XL with BH3-mimetics under conditions of moderate ferroptotic stress in many cases synergistically enhanced overall cell death and frequently skewed primarily ferroptotic into apoptotic outcomes. Surprisingly though, in other cases BH3-mimetics, most notably the BCL-XL inhibitor WEHI-539, counter-intuitively suppressed cell death and promoted cell survival following GPX4 inhibition. Further studies revealed that most BH3-mimetics possess previously undescribed antioxidant activities that counteract ferroptotic cell death at commonly employed concentration ranges. Our results therefore show that ferroptosis and apoptosis can intersect. We also show that combining ferroptotic stress with BH3-mimetics, context-dependently can either enhance and convert cell death outcomes between ferroptosis and apoptosis or can also suppress cell death by intrinsic antioxidant activities.
铁死亡和凋亡被广泛认为是独立的细胞死亡方式。铁死亡性细胞死亡是自由基解毒不足和进行性脂质过氧化的结果，谷胱甘肽过氧化物酶-4（GPX4）可对抗这种情况。凋亡性细胞死亡可由多种应激触发，包括氧自由基，并且可被BCL-2蛋白家族的抗凋亡成员抑制。线粒体是BCL-2家族成员的主要相互作用位点，同样也是氧自由基应激的主要来源。因此，我们研究了铁死亡和凋亡是否可能相互交叉并相互干扰。事实上，因GPX4活性受损而死亡的细胞表现出铁死亡和凋亡性细胞死亡的特征，后者包括（短暂的）细胞膜起泡、次最大程度的细胞色素c释放和半胱天冬酶激活。在中度铁死亡应激条件下，用BH3模拟物靶向BCL-2、MCL-1或BCL-XL，在许多情况下会协同增强总体细胞死亡，并经常使主要的铁死亡偏向凋亡结果。然而，令人惊讶的是，在其他情况下，BH3模拟物，最显著的是BCL-XL抑制剂WEHI-539，与直觉相反地抑制了细胞死亡，并在GPX4抑制后促进了细胞存活。进一步的研究表明，大多数BH3模拟物具有以前未描述的抗氧化活性，可在常用浓度范围内对抗铁死亡性细胞死亡。因此，我们的结果表明铁死亡和凋亡可以相互交叉。我们还表明，将铁死亡应激与BH3模拟物结合，根据具体情况，要么增强并在铁死亡和凋亡之间转换细胞死亡结果，要么也可通过内在抗氧化活性抑制细胞死亡。
