Fig. 3: Regulatory mechanisms of ferroptosis.

The occurrence of ferroptosis involves an increase in PUFAs, Fe²⁺, and reactive oxygen species levels. The synthesis of PUFAs primarily occurs in the endoplasmic reticulum. On one hand, the MUFAs ingested by cells are converted into MUFAs-CoA under the action of ACSL3, which then interacts with Lysop LS to produce MUFAs-PLs, thereby inhibiting PL-OOH. On the other hand, the PUFA intake is converted into FUFAs-CoA under the action of ACSL4, which also interacts with Lysop LS to form FUFAs-PLs, promoting PL-OOH. Additionally, MUFAs can be converted into PUFAs under the influence of FADS1 and FADS2, thus facilitating ferroptosis. Additionally, the transcription factors SREBPs, residing in the endoplasmic reticulum, translocate to the nucleus, activating the expression of SCD1, which catalyzes the synthesis of long-chain monounsaturated fatty acids, thereby reducing membrane susceptibility to peroxidation and sensitivity to ferroptosis. The generation of Fe²⁺ involves the endoplasmic reticulum, mitochondria, and lysosomes. In the endoplasmic reticulum, NFE2L2 acts on VAMP8-NCOA4 to increase free Fe²⁺ levels; iron entering the cell via TFRC is released in the acidic environment of the lysosome, resulting in elevated free Fe²⁺; and increased mitochondrial iron uptake mediated by MFRN1 in the mitochondria can enhance sensitivity to ferroptosis. The production and regulation of ROS primarily involve the antioxidant enzyme system, lipophilic free radical-scavenging antioxidants, and the regulation of ROS by certain organelles. Within the antioxidant enzyme system, GPX4 directly inhibits lipid peroxidation, with its synthesis dependent on cysteine and selenium, thus regulated by the cystine-glutamate reverse transport protein (xc-) that transports cystine, a precursor of cysteine. Additionally, some cysteine and selenium are derived from lysosomes, which are also regulated by lysosomes. Furthermore, selenocysteine is synthesized directly on a specific tRNA (tRNA[Ser]Sec) through a multi-step process that relies on FPP from the endoplasmic reticulum. The main RTAs include CoQ10 and vitamin K, whose reduced forms can reduce reactive oxygen species and inhibit ferroptosis. FSP1, located in the cell membrane, facilitates the reduction of CoQ10 and vitamin K, further inhibiting ferroptosis. In mitochondria, α-KG competes with GPX4 for cysteine, inhibiting ferroptosis; the activation of Oma1 leads to mitochondrial fragmentation and induces an integrated stress response along the Oma1-Dele1-Atf4 signaling axis, which can inhibit ferroptosis and exert a protective role. In the endoplasmic reticulum, POR and CYB5R1 utilize NADPH to produce ROS, promoting lipid peroxidation and ferroptosis; in the mevalonate pathway, 7DHC acts as an endogenous free radical scavenger, limiting lipid peroxidation; GGPP is a key precursor for the synthesis of vitamin K and coenzyme Q, inhibiting ferroptosis. PUFAs polyunsaturated fatty acids, MUFAs monounsaturated fatty acids, ACSL3 Acyl‑CoA synthetase long‑chain family member 3, MUFAs‑CoA monounsaturated fatty acyl‑CoA, PLA2 phospholipase A2, Lysop LS lysophospholipids (lysophospholipids are a form of phospholipids characterized by the retention of only one fatty acid chain in their structure, serving as critical intermediates in phospholipid metabolism), MUFAs‑PLs monounsaturated fatty acyl phospholipids, PL‑OOH phospholipid hydroperoxides, ACSL4 Acyl‑CoA synthetase long‑chain family member 4, FUFAs‑CoA fully unsaturated fatty Acyl-CoA, FUFAs‑PLs polyunsaturated fatty acyl phospholipids, FADS1 fatty acid desaturase 1, FADS2 fatty acid desaturase 2, SREBPs sterol regulatory element‑binding proteins, SCD1 stearoyl‑CoA desaturase 1, NFE2L2 nuclear factor, erythroid 2‑like 2 (NRF2), VAMP8 vesicle‑associated membrane protein 8, NCOA4 nuclear receptor coactivator 4, TFRC transferrin receptor, MFRN1 mitoferrin‑1 (SLC25A37), GPX4 glutathione peroxidase 4, FPP farnesyl pyrophosphate, RTAs radical‑trapping antioxidants, CoQ10 coenzyme Q10, FSP1 ferroptosis suppressor protein 1 (AIFM2), α‑KG alpha‑ketoglutarate (2‑oxoglutarate), OMA1 OMA1 zinc metallopeptidase (mitochondrial OMA1 protease), DELE1 DAP3‑binding cell death enhancer 1, ATF4 activating transcription factor 4, POR cytochrome P450 oxidoreductase, CYB5R1 cytochrome b5 reductase 1, NADPH nicotinamide adenine dinucleotide phosphate (reduced form), 7DHC 7‑dehydrocholesterol, GGPP Geranylgeranyl pyrophosphate.