Table 1.

The main morphologic features, triggers, and players of different forms of PCD

Programmed cell death	Morphologic features	Triggers	Main players Pathways
Apoptosis	ϖ Tight intracellular arrangement of organelles ϖ Cell shrinkage ϖ Nuclear division ϖ Presence of an apoptotic body in the cytoplasm	For the intrinsic route: DNA damage, Endoplasmic reticulum stress, and other endogenous apoptotic signals For the extrinsic route: cell membrane death receptors with death domains, like FADD and TRADD, and external ligands	Intrinsic route (mitochondrial apoptotic pathway): BCL-2 family, BAK, BAX, Bid, cytochrome c, Apaf-1, pro-caspase-9, apoptosome, and dATP Extrinsic pathway: FADD and TRADD, Caspase-8
Pyroptosis	ϖ Pore formation ϖ Cell swelling ϖ Osmotic lysis ϖ Chromatin condensation ϖ DNA breakage ϖ Release of proinflammatory substances	Granzyme-mediated route: GzmB, GzmA Canonical route: PAMPs and DAMPs  Non-canonical route: DAMPs and PAMPs like cytosolic LPS Caspase-3/8-dependent route: hypoxia, chemotherapy agents, inhibition of TAK1 (e.g., by Yersinia)	Granzyme-mediated route: GzmA, GzmB, caspase-3, GSDME, GSDMB, GSDMC, PD-L1, STAT3, Caspases-8, TNFα Canonical route: PAMPs and DAMPs, Sensor proteins, the adaptor protein ASC, pro-caspase-1, IL-1β and IL-18, GSDMD Non-canonical route: LPS, K⁺ efflux, caspase-4/5, GSDMD, NLRP3, IL-1β and IL-18 Caspase-3/8-dependent route: caspase-8, GSDMD
Necroptosis	ϖ Cell swelling ϖ Organelle breakdown ϖ Plasma membrane rupture ϖ Production of DAMPs	TNF-α/TNFR1 pathway: TNF-α binds to TNFR1	TNF-α/TNFR1 pathway: TRADD, TRAF2/5, RIPK1, RIPK3, cIAPs, caspase-8, MLKL
PANoptosis	A mixture of morphological features of apoptosis, pyroptosis, and necroptosis ϖ membrane pore formation ϖ Cell shrinkage or swelling ϖ Nuclear fragmentation	Infection with pathogens such as HSV1, IAV, SARS-CoV2, Yersinia, F.Novicida and their PAMPs, heme, cytokines ZBP1-dependent PANoptosome: Z-RNA generated by DNA and RNA viruses AIM2-dependent PANoptosome: HSV1 or Francisella. novicida (F. novicida) infection RIPK1-dependent PANoptosome: Yersinia infection NLRP3, and NLRP12-dependent PANoptosome: heme and PAMPs	ZBP1-dependent PANoptosome: ZBP1, RIPK1 and RIPK3, ASC/NLRP3/CASP1-GSDMD and CASP3/6/7 and MLKL AIM2-dependent PANoptosome: AIM2, Pyrin, ZBP1, ASC, caspase-1, caspase-8, RIPK1, RIPK3, and FADD RIPK1-dependent PANoptosome: RIPK1 and 3, caspase-8, ASC, NLRP3, and caspase-1 NLRP3, and NLRP12-dependent PANoptosome: NLRP3, NLRP12, ASC, caspase-8, and RIPK3

Abbreviation: BCL-2 Pro-apoptotic members of the B-cell lymphoma 2, BAK BCL2-antagonist/killer 1, BAX BCL2-associated X protein, Apaf-1 Apoptotic protease activating factor-1, dATP: deoxyadenosine triphosphate, FADD Fas-associated death domain protein, TRADD Tumor necrosis factor receptor-associated DEATH domain protein, PAMP Pathogen-Associated Molecular Patterns, DAMP Damage-Associated Molecular Patterns, GSDMD Gasdermin D, IL-1β Interleukin-1β, IL-18 Interleukin-18, LPS lipopolysaccharide, NLRP3 NOD-, LRR-, and pyrin domain-containing protein 3, GzmA granzyme A, GzmB granzyme B, PD-L1 Programmed Cell Death Ligand 1, STAT3 Signal Transducer and Activator of Transcription 3, TNFα Tumor necrosis factor α, TRAF2/5 TNF receptor-associated factor 2/5, RIPK1 Receptor-interacting protein kinase 1, cIAPs cellular inhibitor of apoptosis proteins, MLKL Mixed Lineage Kinase Domain-Like, HSV1 Herpes simplex virus 1, IAV Influenza A virus, PAMP Pathogen associated molecular pattern, DAMP Damage associated molecular pattern, F. Novicida Francisella. Novicida, SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2