Regulated Cell Death Pathways and Their Roles in Homeostasis, Infection, Inflammation, and Tumorigenesis

Overview

Journal Exp Mol Med

Specialties Biochemistry
Molecular Biology

Date 2023 Aug 23

PMID 37612410

Authors

Ein Lee

Chang-Hyun Song

Sung-Jin Bae

Ki-Tae Ha

Rajendra Karki

Affiliations

Soon will be listed here.

Abstract

Pyroptosis, apoptosis, necroptosis, and ferroptosis, which are the most well-studied regulated cell death (RCD) pathways, contribute to the clearance of infected or potentially neoplastic cells, highlighting their importance in homeostasis, host defense against pathogens, cancer, and a wide range of other pathologies. Although these four RCD pathways employ distinct molecular and cellular processes, emerging genetic and biochemical studies have suggested remarkable flexibility and crosstalk among them. The crosstalk among pyroptosis, apoptosis and necroptosis pathways is more evident in cellular responses to infection, which has led to the conceptualization of PANoptosis. In this review, we provide a brief overview of the molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis and their importance in maintaining homeostasis. We discuss the intricate crosstalk among these RCD pathways and the current evidence supporting PANoptosis, focusing on infectious diseases and cancer. Understanding the fundamental processes of various cell death pathways is crucial to inform the development of new therapeutics against many diseases, including infection, sterile inflammation, and cancer.

Citing Articles

Identification and validation of PANoptosis-related LncRNAs prognosis system in hepatocellular carcinoma.

Shu Q, Zhu J, Mo J, Wei X, Zhu Z, Chen X Sci Rep. 2025; 15(1):6030.

PMID: 39972122 PMC: 11840146. DOI: 10.1038/s41598-025-90498-y.

Advances in non-apoptotic regulated cell death: implications for malignant tumor treatment.

Zhang Y, Yi S, Luan M Front Oncol. 2025; 15:1519119.

PMID: 39949740 PMC: 11821507. DOI: 10.3389/fonc.2025.1519119.

Progress in Research on Regulated Cell Death in Cerebral Ischaemic Injury After Cardiac Arrest.

Chen Z, Wang S, Shu T, Xia S, He Y, Yang Y J Cell Mol Med. 2025; 29(3):e70404.

PMID: 39936900 PMC: 11816164. DOI: 10.1111/jcmm.70404.

The recombinant spike S1 protein induces injury and inflammation in co-cultures of human alveolar epithelial cells and macrophages.

Liu Y, Yu H, He J, Li J, Peng D PLoS One. 2025; 20(2):e0318881.

PMID: 39928621 PMC: 11809858. DOI: 10.1371/journal.pone.0318881.

CASC8 activates the pentose phosphate pathway to inhibit disulfidptosis in pancreatic ductal adenocarcinoma though the c-Myc-GLUT1 axis.

Yao H, Ge J, Chen J, Tang X, Li C, Hu X J Exp Clin Cancer Res. 2025; 44(1):26.

PMID: 39865281 PMC: 11771065. DOI: 10.1186/s13046-025-03295-w.

References

Wang Y, Kanneganti T . From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J. 2021; 19:4641-4657. PMC: 8405902. DOI: 10.1016/j.csbj.2021.07.038. View

Green D . The Coming Decade of Cell Death Research: Five Riddles. Cell. 2019; 177(5):1094-1107. PMC: 6534278. DOI: 10.1016/j.cell.2019.04.024. View

Bedoui S, Herold M, Strasser A . Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol. 2020; 21(11):678-695. DOI: 10.1038/s41580-020-0270-8. View

Tang D, Kang R, Vanden Berghe T, Vandenabeele P, Kroemer G . The molecular machinery of regulated cell death. Cell Res. 2019; 29(5):347-364. PMC: 6796845. DOI: 10.1038/s41422-019-0164-5. View

Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M . Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022; 375(6586):1254-1261. PMC: 9273333. DOI: 10.1126/science.abf0529. View

Twiddy D, Cohen G, MacFarlane M, Cain K . Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex. J Biol Chem. 2005; 281(7):3876-88. DOI: 10.1074/jbc.M507393200. View

Stennicke H, Jurgensmeier J, Shin H, Deveraux Q, Wolf B, Yang X . Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem. 1998; 273(42):27084-90. DOI: 10.1074/jbc.273.42.27084. View

Nicholson D, Ali A, Thornberry N, Vaillancourt J, Ding C, Gallant M . Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995; 376(6535):37-43. DOI: 10.1038/376037a0. View

Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H . Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015; 526(7575):660-5. DOI: 10.1038/nature15514. View

10.

Kayagaki N, Stowe I, Lee B, ORourke K, Anderson K, Warming S . Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015; 526(7575):666-71. DOI: 10.1038/nature15541. View

11.

Sun L, Wang H, Wang Z, He S, Chen S, Liao D . Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012; 148(1-2):213-27. DOI: 10.1016/j.cell.2011.11.031. View

12.

Wang H, Sun L, Su L, Rizo J, Liu L, Wang L . Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014; 54(1):133-146. DOI: 10.1016/j.molcel.2014.03.003. View

13.

Stockwell B . Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022; 185(14):2401-2421. PMC: 9273022. DOI: 10.1016/j.cell.2022.06.003. View

14.

Kayagaki N, Kornfeld O, Lee B, Stowe I, ORourke K, Li Q . NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021; 591(7848):131-136. DOI: 10.1038/s41586-021-03218-7. View

15.

Ke F, Vanyai H, Cowan A, Delbridge A, Whitehead L, Grabow S . Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK. Cell. 2018; 173(5):1217-1230.e17. DOI: 10.1016/j.cell.2018.04.036. View

16.

Hakem R, Hakem A, Duncan G, Henderson J, Woo M, Soengas M . Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell. 1998; 94(3):339-52. DOI: 10.1016/s0092-8674(00)81477-4. View

17.

Yoshida H, Kong Y, Yoshida R, Elia A, Hakem A, Hakem R . Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell. 1998; 94(6):739-50. DOI: 10.1016/s0092-8674(00)81733-x. View

18.

Karki R, Sharma B, Tuladhar S, Williams E, Zalduondo L, Samir P . Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2020; 184(1):149-168.e17. PMC: 7674074. DOI: 10.1016/j.cell.2020.11.025. View

19.

Karki R, Lee S, Mall R, Pandian N, Wang Y, Sharma B . ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection. Sci Immunol. 2022; 7(74):eabo6294. PMC: 9161373. DOI: 10.1126/sciimmunol.abo6294. View

20.

Mall R, Bynigeri R, Karki R, Malireddi R, Sharma B, Kanneganti T . Pancancer transcriptomic profiling identifies key PANoptosis markers as therapeutic targets for oncology. NAR Cancer. 2022; 4(4):zcac033. PMC: 9623737. DOI: 10.1093/narcan/zcac033. View