Vitamin A and its analogues modulate MUFAs metabolism to improve ferroptosis and aging by direct targeting of ACSL3

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 [(2 E ,4 E ,6 E ,8 E )- 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. Vitamin A and its analogues target and promote ACSL3 activity, increasing MUFA-PLs synthesis to inhibit lipid peroxidation and ferroptosis, thereby ameliorating acute liver injury and promoting longevity in C. elegans .