α-tocopherol (Vitamin E) inhibits second mitochondria-derived activator of caspases (SMAC) mimetic-induced cell death by directly targeting cIAP1 degradation.

Authors

Jing Zhu, Xiaofang Tian, Yujie Zhao, Fan Yang, Rui Wang, Fang Wang, Zhuhong Wang, Tianle Zhang, Wenqing Ren, Chenxiao Tang, Jingming Ren, Jin Cai, Yuan He, Chenjie Zhu, Xiaona Feng, Yue Liu, Siriporn Jitkaew, Chunlin Zhuang, Yaxing Zhao, Zhenyu Cai

Published in

British journal of pharmacology. Nov 08, 2026. Epub Nov 08, 2026.

Abstract

Tocopherols (vitamin E) are well characterized as essential lipophilic antioxidant agents. However, recent evidence suggests that tocopherols may also regulate cellular signalling through direct interactions with specific protein targets. This study aimed to investigate the molecular mechanism by which α-tocopherol regulates programmed cell death and to identify its direct molecular target.
A high-throughput screen identified α-tocopherol as an inhibitor of TNF-α/SMAC-mimetic-induced cell death. The mechanism(s) underlying this action of α-tocopherol was investigated using western blotting, immunoprecipitation, ubiquitination assays, drug affinity responsive target stability, cellular thermal shift assay, isothermal titration calorimetry and molecular docking. Its efficacy, in vivo, was evaluated in a murine model of ulcerative colitis, induced by dextran sulphate sodium (DSS).
α-Tocopherol selectively inhibited TNF-α/SMAC-mimetic-induced cell death by directly and competitively binding to the BIR3 domain of the inhibitor of apoptosis protein-1 (cIAP1). This interaction stabilized cIAP1, prevented the formation of RIPK1-dependent death complexes and suppressed apoptosis and necroptosis. In a murine model of DSS-induced colitis, α-tocopherol significantly alleviated disease severity while preserving cIAP1 protein expression.
Our findings identified cIAP1 as a previously unrecognized molecular target of α-tocopherol and demonstrated that cIAP1 stabilization contributed to the suppression of RIPK1-dependent cell death. These findings expand the current understanding of the biological functions of tocopherols and provide a mechanistic basis for their potential therapeutic application in inflammatory diseases associated with aberrant cIAP1 degradation.

PMID:
43000179
Bibliographic data and abstract were imported from PubMed on 09 Nov 2026.

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