Ferroptosis

1.1 Mechanism Overview

Ferroptosis is a form of regulated cell death driven by iron‑dependent lipid peroxidation. Its initiation is jointly determined by disrupted iron metabolism, remodeled lipid metabolism and the collapse of antioxidant defense systems. Cells take up iron ions via transferrin receptor (TFRC) and store iron in ferritin. NCOA4‑mediated ferritinophagy expands the labile iron pool (LIP). Subsequently, Fe²⁺ generates abundant reactive oxygen species (ROS) through the Fenton reaction and facilitates the formation of lipid radicals. Meanwhile, ACSL4 and LPCAT3 mediate the biosynthesis of polyunsaturated fatty acid‑containing phospholipids (PUFA‑PLs), enriching cell membranes with oxidation‑prone lipids. Lipid peroxidation occurs under the action of ROS and lipoxygenases (ALOX), leading to accumulation of lipid peroxides (lipid‑OOH) and damage to membrane structures, ultimately triggering ferroptosis.

To maintain redox homeostasis, cells rely on the antioxidant defense axis centered on system Xc⁻ (SLC7A11/SLC3A2)–glutathione (GSH)–GPX4 to eliminate lipid peroxides. In addition, GPX4‑independent pathways including the FSP1–CoQ axis, GCH1–BH4 axis and mitochondrial DHODH–CoQ axis suppress ferroptosis by scavenging lipid radicals. Accordingly, ferroptosis essentially arises from the imbalance among elevated iron load, intensified PUFA lipid peroxidation and impaired antioxidant capacity. TFRC/NCOA4 govern iron supply; ACSL4/LPCAT3 determine cellular susceptibility to lipid oxidation; GPX4, FSP1, GCH1 and DHODH constitute the core anti‑ferroptotic defense network. Collectively, these factors dictate cellular sensitivity to ferroptosis.

Ferroptosis Mechanism Diagram: Ferroptosis is triggered by iron metabolic imbalance‑induced Fe²⁺ accumulation, which generates ROS via the Fenton reaction and facilitates ACSL4/LPCAT3‑mediated peroxidation of PUFA‑containing phospholipids. When antioxidant systems including GPX4–GSH, FSP1–CoQ, GCH1–BH4 and DHODH–CoQ fail to scavenge lipid peroxides, oxidative damage emerges on cell membranes, ultimately inducing iron‑dependent programmed cell death.

1.2 Target List

Mechanism Module	Target (Gene/Protein)	Full Name	Main Function	Effect on Ferroptosis
Iron Uptake	TFRC (TfR1)	Transferrin receptor 1	Mediates cellular uptake of transferrin‑bound iron	↑ Promote ferroptosis
	TF	Transferrin	Delivers Fe³⁺ into cells	↑ Promote ferroptosis
	SLC11A2 (DMT1)	Divalent metal transporter 1	Transmembrane transport of Fe²⁺	↑ Promote ferroptosis
Iron Storage	FTH1	Ferritin heavy chain 1	Sequesters free iron and alleviates Fe²⁺ cytotoxicity	↓ Inhibit ferroptosis
	FTL	Ferritin light chain	Subunit of ferritin complex	↓ Inhibit ferroptosis
Ferritinophagy	NCOA4	Nuclear receptor coactivator 4	Mediates ferritinophagy and triggers Fe²⁺ release	↑ Promote ferroptosis
	LC3B (MAP1LC3B)	Microtubule‑associated protein 1 light chain 3 beta	Autophagy marker protein	↑ Promote ferroptosis
PUFA Metabolism (Lipid Synthesis & Remodeling)	ACSL4	Acyl‑CoA synthetase long‑chain family member 4	Activates PUFAs and facilitates PUFA‑PL formation	↑ Core promoter
	LPCAT3	Lysophosphatidylcholine acyltransferase 3	Incorporates PUFAs into membrane phospholipids	↑ Promote ferroptosis
	ACSL3	Acyl‑CoA synthetase long‑chain family member 3	Mediates MUFA metabolism	↓ Inhibit ferroptosis
	SCD1	Stearoyl‑CoA desaturase 1	Generates MUFAs to mitigate lipid oxidation	↓ Inhibit ferroptosis
	MBOAT1/2	Membrane bound O‑acyltransferase	Catalyzes MUFA‑PE formation	↓ Inhibit ferroptosis
Lipid Oxidation	ALOX5	Arachidonate 5‑lipoxygenase	Catalyzes lipid oxidation	↑ Promote ferroptosis
	ALOX12	Arachidonate 12‑lipoxygenase	Catalyzes PUFA oxidation	↑ Promote ferroptosis
	ALOX15	Arachidonate 15‑lipoxygenase	Accelerates lipid peroxidation	↑ Promote ferroptosis
	POR	Cytochrome P450 oxidoreductase	Boosts ROS production and lipid oxidation	↑ Promote ferroptosis
Core System Xc⁻/GSH/GPX4 Antioxidant Axis	SLC7A11 (xCT)	Solute carrier family 7 member 11	Mediates cystine uptake to sustain GSH synthesis	↓ Inhibit ferroptosis
	SLC3A2	Solute carrier family 3 member 2	Accessory subunit of System Xc⁻	↓ Inhibit ferroptosis
	GCLC	Glutamate‑cysteine ligase catalytic subunit	Rate‑limiting enzyme for GSH synthesis	↓ Inhibit ferroptosis
	GCLM	Glutamate‑cysteine ligase modifier subunit	Regulatory subunit for GSH synthesis	↓ Inhibit ferroptosis
	GSS	Glutathione synthetase	Catalyzes GSH maturation	↓ Inhibit ferroptosis
	GPX4	Glutathione peroxidase 4	Eliminates lipid peroxides (Lipid‑OOH)	↓↓↓ Core suppressor
FSP1‑CoQ Antioxidant System	AIFM2/FSP1	Ferroptosis suppressor protein 1	Promotes CoQ reduction and scavenges lipid radicals	↓ Inhibit ferroptosis
	COQ2	Coenzyme Q2	Participates in CoQ biosynthesis	↓ Inhibit ferroptosis
	COQ7/COQ9	CoQ biosynthesis proteins	Regulates CoQ metabolism	↓ Inhibit ferroptosis
GCH1‑BH4 Antioxidant System	GCH1	GTP cyclohydrolase 1	Rate‑limiting enzyme for BH4 biosynthesis	↓ Inhibit ferroptosis
	PTS	6‑pyruvoyltetrahydropterin synthase	Participates in BH4 biosynthesis	↓ Inhibit ferroptosis
	SPR	Sepiapterin reductase	Supports BH4 regeneration	↓ Inhibit ferroptosis
Mitochondrial Ferroptosis Defense System	DHODH	Dihydroorotate dehydrogenase	Executes mitochondrial CoQ‑dependent antioxidant activity	↓ Inhibit ferroptosis
	GPD2	Glycerol‑3‑phosphate dehydrogenase 2	Modulates mitochondrial CoQ cycling	↓ Inhibit ferroptosis
Iron Homeostasis Regulation	HMOX1 (HO‑1)	Heme oxygenase 1	Degrades heme and liberates iron	Bidirectional regulation
	IREB2	Iron regulatory protein 2	Controls iron homeostasis	↑ Promote ferroptosis
	SLC40A1	Ferroportin	Mediates iron efflux	↓ Inhibit ferroptosis

1.3 Application Scheme

Level	Detection Purpose	Representative Markers
Iron status	Evaluate alterations in iron load	TFRC, FTH1, NCOA4
Lipid oxidation	Assess the execution process of ferroptosis	ACSL4, LPCAT3
Antioxidant capacity	Determine the core mechanism of ferroptosis	GPX4, SLC7A11
Compensatory defense	Identify drug resistance and tolerance mechanisms	FSP1, GCH1, DHODH

1.4 References

1. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron‑dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060‑1072. doi:10.1016/j.cell.2012.03.042.
2. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1‑2):317‑331. doi:10.1016/j.cell.2013.12.010.
3. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91‑98. doi:10.1038/nchembio.2239.
4. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688‑692. doi:10.1038/s41586‑019‑1705‑2.
5. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH‑mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586‑590. doi:10.1038/s41586‑021‑03539‑7.