Medium-Chain Fatty Acids Selectively Sensitize Cancer Cells to Ferroptosis by Inducing CD36 and ACSL4

Overview

Journal Nutrients

Date 2025 Mar 13

PMID 40077664

Authors

Kai Han

Jiaxuan Li

Shutao Yin

Hongbo Hu

Chong Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Inducing ferroptosis in cancer cells is a promising therapeutic strategy. It has been shown that certain types of fatty acids can induce ferroptosis in multiple types of cancer cells.

Methods: Here, we employed crystal violet staining and CCK8 to assess cell viability, a Liperfluo probe and commercial kit to measure lipid peroxides, and western blotting and RNA interference to detect protein levels.

Results: This study demonstrates for the first time that the medium-chain fatty acids lauric acid (LA-m), octanoic acid (OA-m), and decanoic acid (DA-m) selectively sensitize various cancer cell types to ferroptosis induced by either RSL3, a well-known inducer of ferroptosis, or linoleic acid (LA-l), a ω-6 polyunsaturated fatty acid (PUFA). Mechanistically, the ferroptosis-sensitizing effect of medium-chain fatty acids is associated with their ability to upregulate cluster of differentiation 36 (CD36) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression.

Conclusions: These findings suggest that medium-chain fatty acids could be developed as novel ferroptosis sensitizers to enhance ferroptosis-based cancer therapy.

References

Lee J, Kim W, Bae K, Lee S, Lee E . Lipid Metabolism and Ferroptosis. Biology (Basel). 2021; 10(3). PMC: 8000263. DOI: 10.3390/biology10030184. View

Zhang X, Xu Y, Ma L, Yu K, Niu Y, Xu X . Essential roles of exosome and circRNA_101093 on ferroptosis desensitization in lung adenocarcinoma. Cancer Commun (Lond). 2022; 42(4):287-313. PMC: 9017758. DOI: 10.1002/cac2.12275. View

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

Mou Y, Wang J, Wu J, He D, Zhang C, Duan C . Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019; 12(1):34. PMC: 6441206. DOI: 10.1186/s13045-019-0720-y. View

Dierge E, Debock E, Guilbaud C, Corbet C, Mignolet E, Mignard L . Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab. 2021; 33(8):1701-1715.e5. DOI: 10.1016/j.cmet.2021.05.016. View

Li Y, Huang X, Yang G, Xu K, Yin Y, Brecchia G . CD36 favours fat sensing and transport to govern lipid metabolism. Prog Lipid Res. 2022; 88:101193. DOI: 10.1016/j.plipres.2022.101193. View

Tian H, Zhou L, Wang Y, Nice E, Huang C, Zhang H . A targeted nanomodulator capable of manipulating tumor microenvironment against metastasis. J Control Release. 2022; 348:590-600. DOI: 10.1016/j.jconrel.2022.06.022. View

Jiang X, Stockwell B, Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. PMC: 8142022. DOI: 10.1038/s41580-020-00324-8. View

Lin Y, Shen X, Ke Y, Lan C, Chen X, Liang B . Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss. FASEB J. 2022; 36(3):e22147. DOI: 10.1096/fj.202101610R. View

10.

Tang D, Chen X, Kang R, Kroemer G . Ferroptosis: molecular mechanisms and health implications. Cell Res. 2020; 31(2):107-125. PMC: 8026611. DOI: 10.1038/s41422-020-00441-1. View

11.

Chen X, Kang R, Kroemer G, Tang D . Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021; 18(5):280-296. DOI: 10.1038/s41571-020-00462-0. View

12.

Ma W, Sun X, Zhu Y, Liu N . Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. Free Radic Biol Med. 2021; 165:229-242. DOI: 10.1016/j.freeradbiomed.2021.01.033. View

13.

Shi P, Song C, Qi H, Ren J, Ren P, Wu J . Up-regulation of IRF3 is required for docosahexaenoic acid suppressing ferroptosis of cardiac microvascular endothelial cells in cardiac hypertrophy rat. J Nutr Biochem. 2022; 104:108972. DOI: 10.1016/j.jnutbio.2022.108972. View

14.

Zhang H, Hu B, Li Z, Du T, Shan J, Ye Z . PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol. 2022; 24(1):88-98. DOI: 10.1038/s41556-021-00818-3. View

15.

Chen Y, Liao X, Jing P, Hu L, Yang Z, Yao Y . Linoleic Acid-Glucosamine Hybrid for Endogenous Iron-Activated Ferroptosis Therapy in High-Grade Serous Ovarian Cancer. Mol Pharm. 2022; 19(9):3187-3198. DOI: 10.1021/acs.molpharmaceut.2c00333. View

16.

Wang X, Yang Y, Xiao A, Zhang N, Miao M, Wang Z . A comparative study of the effect of a gentle ketogenic diet containing medium-chain or long-chain triglycerides on chronic sleep deprivation-induced cognitive deficiency. Food Funct. 2022; 13(4):2283-2294. DOI: 10.1039/d1fo04087a. View

17.

Li J, Cao F, Yin H, Huang Z, Lin Z, Mao N . Ferroptosis: past, present and future. Cell Death Dis. 2020; 11(2):88. PMC: 6997353. DOI: 10.1038/s41419-020-2298-2. View

18.

Zhang C, Liu X, Jin S, Chen Y, Guo R . Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. 2022; 21(1):47. PMC: 8840702. DOI: 10.1186/s12943-022-01530-y. View

19.

Wang R, Zhang J, Ren H, Qi S, Xie L, Xie H . Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid. Cell Mol Life Sci. 2024; 81(1):85. PMC: 10861707. DOI: 10.1007/s00018-024-05145-y. View

20.

Wen J, Aili A, Yan Y, Lai Y, Niu S, He S . OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis regulating the arachidonic acid metabolism. Front Oncol. 2022; 12:977348. PMC: 9483180. DOI: 10.3389/fonc.2022.977348. View