Cis-monounsaturated fatty acids inhibit ferroptosis through downregulation of transferrin receptor 1

Kai Shan; Guoling Fu; Jiaqi Li; Yumin Qi; Ninghan Feng; Yongsheng Li; Yong Q Chen

doi:10.1016/j.nutres.2023.07.002

Cis-monounsaturated fatty acids inhibit ferroptosis through downregulation of transferrin receptor 1

Nutr Res. 2023 Oct:118:29-40. doi: 10.1016/j.nutres.2023.07.002. Epub 2023 Jul 17.

Authors

Kai Shan¹, Guoling Fu², Jiaqi Li², Yumin Qi³, Ninghan Feng⁴, Yongsheng Li⁵, Yong Q Chen⁶

Affiliations

¹ College of Food Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210000, China; Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, 214122, China.
² Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, 214122, China.
³ Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214122, China; Department of Urology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu Province, 214000, China.
⁴ Department of Urology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu Province, 214000, China.
⁵ Zhejiang Tianxiazhengfang Agricultural Development Limited, Wucheng Linjiang Industrial Park 1, Jinhua, Zhejiang Province, 321000, China.
⁶ Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, 214122, China. Electronic address: yqchen@jiangnan.edu.cn.

PMID: 37544230
DOI: 10.1016/j.nutres.2023.07.002

Abstract

Ferroptosis, a form of cell death mediated by lipid peroxidation, is implicated in various pathological processes. Although monounsaturated fatty acids (MUFAs) can inhibit ferroptotic lipid peroxidation, the underlying structural mechanism of this antagonistic effect remains poorly understood. We hypothesized that MUFAs with different structures (including chain length, conformation, and double bond position) may affect their regulatory effect on ferroptosis. In this study, 11 MUFAs with varying structures were screened to identify those with an inhibitory effect on ferroptosis. Results from 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide assays indicated that only exogenous MUFAs with cis-conformation and centered double bond could inhibit ferroptosis. Meanwhile, it was found that suppressing the expression of SCD1 and SCD5 genes could sensitize cells to ferroptosis indicating the protective role of endogenous MUFA against ferroptosis. Additionally, western blot analysis revealed that cis-MUFAs with centered double bond downregulated the protein levels of transferrin receptor 1. Flow cytometry confirmed that these MUFAs led to decreases in intracellular iron, reactive oxygen species, and lipid peroxides. It was also found that SCD1 inhibitor could enhance ferroptosis inducer-mediated tumor suppression both in vivo and in vitro. Overall, these findings shed light on the particular structural features of MUFAs that contribute to their ferroptosis-resistant properties and suggest the potential therapeutic relevance of natural MUFAs in a range of ferroptosis-related diseases.

Keywords: Conformation; Ferroptosis; Monounsaturated fatty acid; Transferrin receptor 1; Unsaturated bond.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Death
Down-Regulation
Fatty Acids / pharmacology
Fatty Acids, Monounsaturated* / pharmacology
Ferroptosis*
Receptors, Transferrin / metabolism

Substances

Fatty Acids, Monounsaturated
Receptors, Transferrin
Fatty Acids