Ferroptosis Regulated by Hypoxia in Cells

Abstract

Ferroptosis is an oxidative damage-related, iron-dependent regulated cell death with intracellular lipid peroxide accumulation, which is associated with many physiological and pathological processes. It exhibits unique features that are morphologically, biochemically, and immunologically distinct from other regulated cell death forms. Ferroptosis is regulated by iron metabolism, lipid metabolism, anti-oxidant defense systems, as well as various signal pathways. Hypoxia, which is found in a group of physiological and pathological conditions, can affect multiple cellular functions by activation of the hypoxia-inducible factor (HIF) signaling and other mechanisms. Emerging evidence demonstrated that hypoxia regulates ferroptosis in certain cell types and conditions. In this review, we summarize the basic mechanisms and regulations of ferroptosis and hypoxia, as well as the regulation of ferroptosis by hypoxia in physiological and pathological conditions, which may contribute to the numerous diseases therapies.

Keywords: ferroptosis; hypoxia; hypoxia-inducible factors; iron metabolism; lipid peroxidation.

Figure 1

Ferroptosis is caused by the abnormal increased iron accumulation, lipid peroxidation, and dysregulation of antioxidant defense systems. There are complex regulations among iron metabolism, lipid metabolism, and the antioxidant defense system, and they cooperate with each other leading to lipid peroxidation and the occurrence of ferroptosis. Cys: cysteine; Cys-Cys: cystine; Cys-Gly: cysteinylglycine; Glu: glutamate; GGC: Gamma-Glu-Cys; GSSG: glutathione oxidized; LD: lipid droplet; PL: phospholipid; SFA: saturated fatty acid; and Try: tryptophan.

Figure 2

The mechanism of ferroptosis inhibited by hypoxia and HIFs in cells. In tumor cells, hypoxia activates HIF-1α in both canonical and non-canonical ways, to transcriptionally upregulate the expression of CA9, TFRC, GPX4, METTL14, PDK1, BNIP3, FABP3, FABP7, lncPMAN, and lncCBSLR, as well as increase protein levels of ANGPTL4, ferritin, SLC7A11, and GPX4, and decrease protein levels of TRFC and ACSL4, leading to the reduction in free Fe²⁺, ROS, and lipid peroxidation, and eventually inhibiting ferroptosis. In normal cells, hypoxia induces HIF-2α, HIF-1α, SENP1, OTUB1, HSPB1, and miR-210-3p, and represses NCOA4, to regulate FTMT, ferritin, TRFC, ACSL4, GPX4, SLC7A11, and ultimately inhibits ferroptosis. The gray arrows indicate the protein translation process from their corresponding mRNAs.

Figure 3

The mechanism of ferroptosis promoted by hypoxia, HIFs, or H/R in cells. In normal cells, hypoxia activates HIF-1α, HIF-2α, FOXC1, sp1, USP7, p53, CBX7, DNMT-1, USP11, TMEM16A, Beclin-1, and miR-30b-5p, and represses NRF2, SMAD7, and Pax3, to regulate SLC7A11, PTGS2, ACSL4, TF, FPN1, HO-1, TFRC, ZIP8, ZIP14, NCOA4, Hamp1, ELAVL1, SOD, GPX4, and ferritin, resulting in the induction of ferroptosis. In tumor cells, hypoxia regulates HILPDA, ACSL4, PTGS2, and CHAC1 by HIF-2α, TFRC, and DMT1 by HIF-1α and protein CA9 by E2F7/QKI/circBCAR/miR-27a-3p/TNPO1 to promote ferroptosis.