Leak Logan, Wang Ziwei, Joseph Alby J, Johnson Brianna, Chan Alyssa A, Decosto Cassandra M, Magtanong Leslie, Ko Pin-Joe, Lee Weaverly Colleen, Ritho Joan, Manukian Sophia, Millner Alec, Chitkara Shweta, Salinas Jennifer J, Skouta Rachid, Rees Matthew G, Ronan Melissa M, Roth Jennifer A, Myers Chad L, Moffat Jason, Boone Charles, Bensinger Steven J, Nathanson David A, Atilla-Gokcumen G Ekin, Moding Everett J, Dixon Scott J
Department of Biology, Stanford University, Stanford, CA, USA.
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
Nat Chem Biol. 2025 May 26. doi: 10.1038/s41589-025-01913-4.
Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain fatty acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.
诱导非凋亡性细胞死亡的小分子具有重要的机制研究意义，可能对治疗某些癌症有用。在此我们报告，正在进行人体临床试验的候选药物替加维文特可激活肉瘤和其他癌细胞中一种独特的非凋亡性细胞死亡机制。这种致死机制不同于铁死亡、坏死性凋亡和炎性小体介导的细胞焦亡，需要脂质代谢酶反式-2,3-烯酰辅酶A还原酶（TECR）。TECR通常参与超长链脂肪酸的合成，但似乎通过合成饱和长链脂肪酸棕榈酸酯来促进对CIL56和替加维文特的非凋亡性细胞死亡反应。这些发现概述了一种脂质依赖性非凋亡性细胞死亡机制，该机制可由目前正在人体试验的候选药物诱导产生。
