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Table 1 The main morphological features, regulators, inducers and inhibitors of ferroptosis, apoptosis, necroptosis, autophagy-dependent cell death and pyroptosis

From: Targeting ferroptosis in breast cancer

Cell Death Defining Morphological Features Biochemical Features Key Regulators Inducers Inhibitors
Ferroptosis Mitochondria become smaller, with increased mitochondrial membrane densities and reduced mitochondrial crista, outer mitochondrial membrane rupture and normal nucleus [4] Iron accumulation; lipid peroxidation; ΔΨm elevated; caspase-independent [22] GPX4 [23], p53 [24,25,26], HSPB1 [27, 28], SLC7A1 1[4], NRF2 [29,30,31], TFRC [14, 32], NCOA4 [16, 33], ACSL4 [17, 34,35,36], FSP1 [37] GPX4 inactivation due to GSH depletion (class I FINs): erastin [4, 13], erastin derivatives (piperazine erastin [23], imidazole ketone erastin [15]), DPI2 [23], buthionine sulfoximine [23], sulfasalazine [4, 38], sorafenib [39], glutamate [4], cyst(e) inase [40], BAY 87–2243 [41, 42];
GPX4 inactivation/depletion (class II, III FINs): 1S,3R-RSL3 [4, 14, 23], DPI7/ML162, DPI10/ML210, DPI12, DPI13, DPI17, DPI18, DPI19 [23, 43], altretamine [44], FIN56 [45, 46], withaferin A [47], fluvastatin, lovastatin acid, simvastatin [48];
Iron loading (class IV FINs): hemoglobin [49], FeCl2 [49], hemin [47], (NH4)2Fe(SO4)2 [47], non-thermal plasma [50], salinomycin [51], amino acid depletion +Cornell dots [52], lapatinib + siramesine [12], FINO2 [45], BAY 11–7085 [53];
others: lanperisone [54], artemisinin derivatives [55, 56], CIL41, CIL56, CIL69, CIL70, CIL75, and CIL79 [46]
Iron chelators: desferoxamine [4], solamine [4], 2, 2- Bipyridyl [4];
Anti-oxidants: vitamin E [23], U0126 [4, 23], Trolox [4];
ROS formation inhibitors: ferrostatin-1 [4], SRS8–72 [4], SRS11–92, SRS12–45,SRS13–35, SRS13–37 [57], SRS16–86 [58];
Others: cycloheximide [4], aminooxyacetic acid [4], ebselen [4, 59], β-mercaptoethanol [4, 60]
Apoptosis Plasma membrane blebbing; cellular and nuclear volume reduction; chromatin agglutination, nuclearfragmentation;
formation of apoptotic bodies and cytoskeletal disintegration, no significant changes in mitochondrial structure [61]
Activation of caspases; DNA fragmentation; ΔΨm dissipation; phosphatidylserine exposure [22] CASP2, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, CARD8, GZMB, HSPA1B, CARD6, NOX5, p53, Bax, Bak, BCL2 family (e.g., BAK1, BAX, BOK, BCL2L11, BBC3, PMAIP1, BID, BCL2, BCL2L1, MCL1, BCL2L2, and BCL2L10), Bcl-XL [19, 62] Extrinsic apoptosis: FASL, DCC,
Intrinsic apoptosis: multiple intracellular stress conditions
(e.g. DNA damage, cytosolic Ca2+ overload) [61]
Inhibitors of apoptosis (IAPs): XIAP, c-IAP1, c-IAP2, ILP-2, ML-IAP/livin, NAIP, Bruce/Apollon, survivin [63];
caspase inhibitors: Z-VAD-FMK, emricasan, Q-VD-OPh, Z-VAD (OH)- FMK, Z-DEVD-FMK, Z-VDVAD-, ivachtin, Q-DEVD-OPh, Ac-DEVD-CHO, Z- IETD-FMK, Q-LEHD-OPh [22]
Necroptosis Plasma membrane breakdown, generalized swelling of the cytoplasm and organelles, moderate chromatin condensation [61] Drop in ATP levels; activation of RIPK1, RIPK3, and MLKL; cytosolic necrosome formation [5, 22] RIP1, RIP3, MLKL, ESCRT-III, cIAPs, LUBAC, PPM1B, and AURKA [19, 22, 64] TNFα, z-VAD-fmk [19] RIP1 inhibitor: Necrostatin1 (Nec-1 )[65];
MLKL inhibitor: necrosulfonamide (NSA) [65];
RIPK3 inhibitors: GSK872, HS-1371 [65]
Autophagy-dependent cell death Formation of double-membraned autolysosomes, including macroautophagy, microautophagy and chaperone-mediated autophagy [61] MAP 1 LC3B-I to MAP 1LC3B-II conversion; increased autophagic flux and lysosomal activity [5, 22] Beclin 1, ATG family proteins, LC3, DRAM3, TFEB, Na+/K+-ATPase, AMPK, mTOR [5, 19, 22, 66] Rapamycin, lithium, sodium, valproate, carbamazepine [67] Non-selective PI3K inhibitors: 3-methyladenine, LY294002, wortmannin;
Selective VPS34 inhibitors: PIK-III, compound 31, SAR 405, Vps34-In1;
Specific ULK1 inhibitors: MRT68921, MRT67307, SBI-0206965;
Specific Beclin1 inhibitors: Spautin-1 Lysosome inhibitors: chloroquine, hydrochloroquin;
lysosomal inhibitor: Chloroquine;
H+-ATPase inhibitors: bafilomycin A1, concanamycin A;
USP10 and USP13 inhibitor: spautin 1 [22, 68]
Pyroptosis Lack of cell swelling; rupture of plasma membrane; bubbling; moderate chromatin condensation [61] Activation of CASP1, CASP4, CASP5 (CASP1 and CASP11 in mice) and GSDMD; GSDMD cleavage; GSDMD-N–induced pore formation; IL1β and IL18 release [69] CASP1, CASP4, CASP5 (CASP1 and CASP11 in mice) and GSDMD, GPX4, ESCRT-III, PKA [70] Metformin, anthocyanin, DHA, DPP8/9 inhibitor, α-NETA, cisplatin, paclitaxel, iron, L61H10, BI2536, lobaplatin, doxorubicin [69] CASP1 inhibitors: Ac-YVAD-cmk, Z-YVAD (OMe)-FMK, VX765;
CASP11 inhibitor: wedelolactone;
NLRP3-inflammasome inhibitors: MCC950, isoliquiritigenin, glybenclamide, CY-09, oridonin;
GSDMD cleavage inhibitor: Ac-FLTD-CMK [22]