Molecular regulatory mechanism of ferroptosis and its role in gastrointestinal oncology: Progress and updates

Table 1 Common ferroptosis inducers

Target	Inducer	Function	Ref.
System Xc-	Erastin	Inhibits the activity of System Xc- and affects the synthesis of GSH; binds to VDAC2/3 to induce mitochondrial dysfunction	[3,6]
	Erastin analogs, piperazine erastin, imidazole ketone erastin	Inhibits the activity of System Xc- and affects the synthesis of GSH	[103,104]
	Sulfasalazine	Inhibits the activity of System Xc- (weaker inhibitory effect than erastin)	[3,105,106]
	Sorafenib	Inhibits the activity of System Xc- (directly affects the synthesis of GSH in a narrow concentration range)	[107]
	Glutamate	Inhibits the activity of System Xc-, high extracellular glutamate concentrations prevent cystine import	[3,7]
GPX4	(1S,3R)-RSL3	Covalently binds to the selenocysteine residue of GPX4	[5,26]
	DPI7 (ML162), DPI12, DPI17	Covalently bind to GPX4 (at the same binding site as RSL3)	[7,26]
	DPI10 (ML120), DPI13	Indirectly inhibit GPX4 activity or bind to a site different from RSL3	[26,103]
	FIN56	Induces GPX4 degradation; binds and activates SQS to deplete CoQ10	[108]
	Altretamine	Inhibits the activity of GPX4	[64]
GSH	BSO	GSH depletion	[7,103]
	Cisplatin	Binds to GSH to inactivate GXP4	[109]
	DPI2	Depletes GSH	[7,103]
	Cysteinase	Depletes cysteine, resulting in GSH depletion	[7]
	Piperlongumine	Depletes GSH and inhibits the activity of GXP4	[7,64]
ROS and iron	FINO2	Oxidizes Fe2+ ions and promotes intracellular accumulation of ROS; indirectly inactivates GPX4; directly oxidizes PUFAs	[110]
	Ferric ammonium citrate	Increases iron abundance	[7]
	Silica-based nanoparticles	Delivers iron into cells and reduce GSH abundance	[7]
	Heme	Upregulates HMOX1 expression and increases the intracellular level of labile iron	[111]
	ART, DHA	Oxidize Fe2+ ions and promote intracellular accumulation of ROS; induce ferritinophagy and the release of labile iron	[7,51,65]
	Siramesine and lapatinib	Downregulate FPN expression and upregulate TRF expression to increase intracellular labile iron levels	[112]

ART: Artesunate; DHA: Dihydroartemisinin; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HMOX1: Heme oxygenase 1; PUFAs: Polyunsaturated fatty acids; ROS: Reactive oxygen species; SQS: Squalene synthase; VDAC: Voltage-dependent anion channel.

Table 2 Common ferroptosis inhibitors

Target	Inhibitors	Function	Ref.
Lipid peroxidation	Vitamin E, α-tocopherol, trolox, tocotrienols	Block propagation of lipid peroxidation, may inhibit lipoxygenases	[7]
	Deuterated polyunsaturated fatty acids	Block initiation and propagation of lipid peroxidation	[7]
	Butylated hydroxytoluene, butylated hydroxyanisole	Block lipid peroxidation	[7]
	Ferrostatins, liproxstatins	Scavenge ROS and inhibit lipid peroxidation; regulate the expression of oxidation-related proteins	[7]
	CoQ10, idebenone	Block lipid peroxidation	[7]
	Baicalein, PD-146176, AA-861, zileuton	Block lipoxygenase-induced lipid peroxidation	[7]
	Troglitazone	Specifically inhibits ACSL4	[12]
	Zileuton	Specifically inhibits LOX	[113]
	Vildagliptin, alogliptin, linagliptin	Block DPP4-mediated lipid peroxidation	[7,49]
Iron	Deferoxamine, cyclipirox, deferiprone	Deplete iron and prevent iron-dependent lipid peroxidation	[7]
	Nitrogen oxides	Block the Fenton reaction and inhibit the production of hydroxyl radicals	[114]
	Curcumin	Chelates iron to reduce iron accumulation; activates the Nrf2 signaling pathway	[115]

ACSL4: Acyl-CoA synthase long-chain family member 4; LOX: Lipoxygenase; ROS: Reactive oxygen species.