Multifaceted interplays between the essential players and lipid peroxidation in ferroptosis

Conghe Liu; Zhihao Liu; Zheng Dong; Sijin Liu; Haidong Kan; Shuping Zhang

doi:10.1016/j.jgg.2025.01.009

Multifaceted interplays between the essential players and lipid peroxidation in ferroptosis

J Genet Genomics. 2025 Jan 23:S1673-8527(25)00024-4. doi: 10.1016/j.jgg.2025.01.009. Online ahead of print.

Authors

Conghe Liu¹, Zhihao Liu², Zheng Dong¹, Sijin Liu¹, Haidong Kan³, Shuping Zhang⁴

Affiliations

¹ Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
² Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
³ School of Public Health, Key Lab of Public Health Safety of the Ministry of Education and NHC Key Lab of Health Technology Assessment, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China.
⁴ Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China. Electronic address: spzhang@sdfmu.edu.cn.

PMID: 39862922
DOI: 10.1016/j.jgg.2025.01.009

Abstract

Ferroptosis, a type of programmed cell death, represents a distinct paradigm in cell biology. It is characterized by the iron-dependent accumulation of reactive oxygen species, which induce lipid peroxidation (LPO), and is orchestrated by the interplay between iron, lipid peroxides, and glutathione. In this review, we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis, including iron intake and export as well as ferritinophagy, and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases, especially P450 oxidoreductases, in modulating LPO. We summarize how various types of fatty acids (FAs), including saturated, monounsaturated, and polyunsaturated FAs, differentially influence ferroptosis when incorporated into phospholipids. Furthermore, we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis, shedding light on therapeutic avenues for ferroptosis-associated diseases.

Keywords: Fatty acids; Ferroptosis; Flavoprotein oxidoreductases; Lipid peroxidation; Radical-trapping antioxidants.

Publication types

Review