fig2

Figure 2. NFE2L2-dependent genes in ferroptosis. Ferroptosis, a form of oxidative cell death, can be triggered by increased iron accumulation or the inhibition of antioxidant systems. Fe³⁺ is taken up by TFRC and exported by SLC40A1. Inside the cell, Fe³⁺ is reduced to Fe²⁺, with excess iron stored in ferritin (composed of FTH1 and FTL) or sequestered by MT1G. Conversely, autophagic degradation of ferritin via NCOA4 can elevate the labile iron pool, a process regulated by HERC2-mediated degradation of NCOA4 through the ubiquitin-proteasome system. HMOX1 also contributes to the labile iron pool by catalyzing heme degradation. Iron is utilized in mitochondria for heme synthesis via FECH and ABCB6 or transported to the nucleus by PIR, which suppresses autophagy by limiting the cytosolic translocation of HMGB1. Excess iron can lead to oxidative stress and ROS production via the Fenton reaction, which can be countered by NQO1, HMOX1, or G6PD. ACSL4 is a key regulator of ferroptosis, producing PUFAs for subsequent ALOX-mediated lipid peroxidation. MGST1 inhibits ALOX activity through direct interaction, while MUFAs may competitively inhibit PUFA lipid peroxidation. Multiple mechanisms inhibit excessive lipid peroxidation, with GPX4 playing a central role by using GSH to neutralize lipid peroxides. GSH levels are positively regulated by the system xc^--mediated cystine uptake and subsequent cysteine production, with SLC7A11 and SLC3A2 as key components. GCL (composed of GCLC and GCLM) is the rate-limiting enzyme in GSH synthesis, and GSSG can be reduced back to GSH by GSR. AIFM2 provides a GPX4-independent anti-ferroptotic pathway through various mechanisms, including the production of CoQ10 or vitamin K, or activation of ESCRT-III membrane repair pathways. 4-HNE, an end product of lipid peroxidation, is detoxified by the ALDH family. NFE2L2-dependent genes are highlighted in green, while positive regulators of ferroptosis are shown in red. NFE2L2: NFE2-like basic leucine zipper transcription factor 2; TFRC: transferrin receptor; SLC40A1: solute carrier family 40 member 1; FTH1: ferritin heavy chain 1; FTL: ferritin light chain; MT1G: metallothionein 1G; NCOA4: nuclear receptor coactivator 4; HERC2: HECT and RLD domain containing E3 ubiquitin protein ligase 2; HMOX1: heme oxygenase 1; FECH: ferrochelatase; ABCB6: ATP-binding cassette subfamily B member 6; PIR: pirin; HMGB1: high mobility group box 1; ROS: reactive oxygen species; NQO1: quinone oxidoreductase-1; G6PD: glucose-6-phosphate dehydrogenase; ACSL4: acyl-CoA synthetase long-chain family member 4; PUFAs: polyunsaturated fatty acids; ALOX: lipoxygenase; MGST1: microsomal glutathione S-transferase 1; MUFAs: monounsaturated fatty acids; GPX4: glutathione peroxidase 4; GSH: glutathione; GCL: glutamate-cysteine ligase; GCLC: glutamate-cysteine ligase catalytic subunit; CGLM: glutamate-cysteine ligase modifier subunit; GSSG: oxidized glutathione; GSR: glutathione reductase; AIFM2: apoptosis-inducing factor mitochondria-associated 2; CoQ10: coenzyme Q10; ESCRT-III: endosomal sorting complex required for transport-III; 4-HNE: 4-hydroxynonenal; ALDH: aldehyde dehydrogenase.