TY - JOUR
T1 - Retinol Saturase Mediates Retinoid Metabolism to Impair a Ferroptosis Defense System in Cancer Cells
AU - Bi, Guoshu
AU - Liang, Jiaqi
AU - Shan, Guangyao
AU - Bian, Yunyi
AU - Chen, Zhencong
AU - Huang, Yiwei
AU - Lu, Tao
AU - Li, Ming
AU - Besskaya, Valeria
AU - Zhao, Mengnan
AU - Fan, Hong
AU - Wang, Qun
AU - Gan, Boyi
AU - Zhan, Cheng
N1 - Funding Information:
The authors thank Dr. Jing Wu for providing liposomes. The authors thank Home for Researchers (www.home-for-researchers.com) for editing the article. They thank OE Biotech Co., Ltd. (Shanghai, China) for their assistance on lipidomics, single-cell RNA-seq, and bioinformatic analysis. This research was supported by the Natural Science Foundation of Shanghai (no. 22ZR1411900 to C. Zhan) and the Special Foundation for Supporting Biomedical Technology of Shanghai (no. 22S11900300 to C Zhan). The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Funding Information:
The authors thank Dr. Jing Wu for providing liposomes. The authors thank Home for Researchers (www.home-for-researchers.com) for editing the article. They thank OE Biotech Co., Ltd. (Shanghai, China) for their assistance on lipidomics, single-cell RNA-seq, and bioinformatic analysis. This research was supported by the Natural Science Foundation of Shanghai (no. 22ZR1411900 to C. Zhan) and
Funding Information:
B. Gan reports personal fees from Guidepoint Global, Cambridge Solutions, and NGM Bio outside the submitted work. C. Zhan reports grants from Natural Science Foundation of Shanghai and Special Foundation for Supporting Biomedical Technology of Shanghai during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
©2023 American Association for Cancer Research.
PY - 2023/7
Y1 - 2023/7
N2 - Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/ Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one. Significance: Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.
AB - Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/ Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one. Significance: Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.
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U2 - 10.1158/0008-5472.CAN-22-3977
DO - 10.1158/0008-5472.CAN-22-3977
M3 - Article
C2 - 37184371
AN - SCOPUS:85164843184
SN - 0008-5472
VL - 83
SP - 2387
EP - 2404
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -