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 DeathDefining Morphological FeaturesBiochemical FeaturesKey RegulatorsInducersInhibitors
| 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] |