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论文名称：
Vitamin A and its analogues modulate MUFAs metabolism to improve ferroptosis and aging by direct targeting of ACSL3
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发表刊物：
Acta Pharmaceutica Sinica B
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关键字：
Vitamin A, All-trans retinoic acid, Ferroptosis, ACSL3, Lipid metabolism, Acute liver injury, Aging, Longevity
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摘要：
In our screening campaign for novel ferroptosis inhibitors, we identified that vitamin A (VA) and its metabolite all-trans retinoic acid (ATRA) exhibited potent ferroptosis-suppressing activity. Notably, through a combination of biochemical and pharmacological assays, we demonstrated that the anti-ferroptotic effects of VA and ATRA are independent of both antioxidative mechanisms and the canonical RAR/RXR signaling pathway. This conclusion was corroborated by a series of newly synthesized VA analogues. Furthermore, VA and its structural derivatives significantly alleviated ferroptosis-associated pathological phenotypes in murine models. Intriguingly, we discovered a novel function of VA and its analogues, which directly target acyl-CoA synthetase long-chain family member 3 (ACSL3) and enhance its enzymatic activity. This ACSL3-dependent mechanism increases the MUFA/PUFA ratio in phospholipids, thereby preventing lipid peroxidation. Strikingly, we further demonstrated that VA and its analogue D3 [(2E,4E,6E,8E)-N,3,7-trimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamide] extend the lifespan of C. elegans in a manner dependent on ACSL3, highlighting the physiological relevance of this pathway in aging. Collectively, our findings unveil a previously unrecognized role for VA and its analogues in modulating lipid metabolism, thereby providing a theoretical basis for their potential application in treating ferroptosis-related diseases and possibly enhancing longevity.
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第一作者：
Nanxuan Luo,Yijie Xiao,翟义乐
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通讯作者：
张哲,Shenyou Nie,Haixin Yuan
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全部作者：
Jie Li,Lijie Lv,Houhua Yin,Fang Lin,Biwen Wan,Ke Zhang,Junchi Hu,Junyan Liu,Yongjun Dang,Yi He,Yahui Zhao
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是否译文：
否
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发表时间：
2025-11
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收录刊物：
SCI
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发布期刊链接：
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发布时间：
2025-11-07
En
