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. 2022 Oct 22;23(21):12714. doi: 10.3390/ijms232112714

Table 2.

Role of necroptosis in human pathological diseases.

No. Pathological Diseases Disease Models Involvement of Necroptosis References
1 Neurological disease Multiple sclerosis Postmortem brain tissue samples of human patients; RIPK3−/− and Cuprizone-induced MS mice model Increased RIPK1/-3 expression in microglia and macrophages in both human and mouse brain samples,Reduced cleaved caspase-8 expression [69,70]
EAE mice model NF-κβ signaling mediated inflammatory response promotes FLIPL expression leading to necroptosis without caspase-8 activation [70,71,72]
Elevated expression of RIPK1, increased RIPK3 and MLKL phosphorylation in both microglia and oligodendrocytes primarily localized in the white matter of brain. [70,73]
Amyotrophic sclerosis SOD1G93A-mutated mice Increased levels of RIPK1 and RIPK3 in MNs and astrocytes primarily localized in the spinal cord [74,75,76]
Optn−/− mice Elevated levels of RIPK1, RIPK3 and pMLKL and necroptosis in the MNs of spinal cord [76]
TBK1−/− mice; TBK1−/− cell line Higher level of RIPK1 and TNF-α induced necroptosis [77,78]
Alzheimer’s disease Postmortem brain tissue samples and 23 AD, 24 p-preAD brain tissue samples from human patients; 5xFAD mice model Elevated level of RIPK1/-3/MLKL at both mRNA and protein level [79,80,81]
Tg2576 APP/PS1 mice model Higher RIPK1 activation drives Cst7 expression in microglia leads to lysosomal dysfunction and blocked proteostasis of deposit Aβ-plaques in AD [80,82]
cpdm mice model Attenuation of M1 ubiquitination of RIPK1 to stimulate its activation [83]
Parkinson’s disease OPA1-mutant PD patients derived iPSC; OPA1-A495V and OPA1-G488R neuronal cell lines Higher phosphorylation level of RIPK1/-3/MLKL and mitochondrial dysfunction-induced necroptosis [84]
PD models (PC12 & SH-SY5Y cell line; 6-OHDA & MPTP mice model) Promotes necrosome complex formation (RIPK1/-3/MLKL),ROS stimulated RIPK1 activation following with ASK1/JNK signaling activation [84,85,86]
2 Renal disease I/R-induced AKI IRI C57BL/6 mouse model RIPK3- and CypD and PPIF mediated mPT-dependent necroptosis [87,88,89]
Toxicant-induced AKI FA-AKI renal mouse model RIPK3/MLKL- and TWEAK-Fn14 axis-induced necroinflammation mediated necroptosis [90,91]
Cisplatin & Oxalate crystals nephrotoxicant mice model RIPK3- and CypD-induced necroinflammation mediated necroptosis in the renal proximal tubular epithelial cells and whole kidney lysates,MLKL dependent necroptosis via higher MLKL membrane association in oxalate crystal-treated renal PTC cells [92,93,94,95]
Sepsis-induced AKI CLP C57BL/6N mice model RIPK3 induced higher OS and mitochondrial dysfunction via upregulation of NOX4 and mitochondrial complex-I/III inhibition [96]
Renal fibrosis CKD RIPK3−/− UUO and AD fibrosis mice model RIPK3 exacerbates kidney fibrogenesis via the PI3K-AKT dependent activation of ACL metabolic activity [95]
IRI mice model; OGBD treated PTC cell line RIPK3/MLKL-dependent necroptosis mediated necroinflammation promotes renal interstitial fibrogenesis [97]
3 Hepatic disease Alcoholic liver disease Chronic alcoholic mice model CYP2E1-mediated higher RIP3 expression induces hepatocyte necroptosis during chronic alcohol treatment [98]
Gao-binge (chronic alcoholic) mice model Impaired hepatic proteasome function via chronic alcohol exposure led to the higher accumulation of RIPK3 and induced necroptosis [99,100]
NAFLD and NASH diseases HFCD and MCD diet mice model TNF-α mediated RIPK3-dependent necroptosis, -oxidative stress and -necroinflammation in mice liver lysates [101,102,103,104]
FFC diet mice model MLKL-dependent necroptotic signaling promotes FFC diet-induced liver injuries and necroinflammation via autophagy-flux inhibition [105]
4 Pulmonary disease Acute lung injuries (ALI) VILI- induced ALI mice model Impaired mitochondria-FAO metabolism pathway via MV exposure led to the RIPK3-dependent necroptosis mediates ALI pathogenesis [106]
LPS/ATP-induced ALI mice model RIPK3 mediated NLRP3 inflammasome activation promotes lung injury via markedly increase inflammatory cell influx,IL-1α/β, IL-6, IL-18 secretion and HMGB1 release in infiltrating macrophages/monocytes cells 133
Acute respiratory distress syndrome Oleic acid-fed SD rat ARDS model Elevated expression of TNF-α and RIPK1, RIPK3, MLKL in the BALF and lung tissue of OA-fed SD rat [107]
LPS-induced ARDS mice model RIPK3-dependent necroptosis enhanced necroinflammation, ROS overgeneration and lung tissue injuries via increasing neutrophil infiltration and cytokines secretion in lung parenchyma tissue [108,109]
Sepsis/systemic inflammatory associated disorder (SIRS) TNF-α induced SIRS mice model RIPK1/-3 induced necroptosis with the DAMPs release and pro-inflammatory cytokines secretion associated with higher systemic inflammation and polymicrobial sepsis [109]
Cecal slurry-induced neonatal sepsis C57BL/6 mouse model Elevated expression of RIPK1 and RIPK3 associated with systemic and pulmonary inflammation and lung injuries in neonatal sepsis [110,111]
Chronic obstructive pulmonary disease Cigarette smoke (CS)-exposed Beas-2B cells and - C57BL/6 mice model CS-induced mitoROS, mitochondrial dysfunction and mitophagy leads to necroptotic signaling activation with necroinflammation in pulmonary epithelial cells and alveolar macrophages [112,113,114,115,116]
Idiopathic pulmonary fibrosis (IPF) BLM-induced IPF mice model RIPK3 mediated necroptosis and DAMPs release induced necroinflammation and lung injury via increasing neutrophil infiltration and cytokines secretion in the alveolar epithelial cells [117]
5 Cardiovascular disease Heart failure I/R or cardiotoxicant (doxorubicin) induced cardiac injury murine and pig model Elevated level of RIPK1, RIPK3 and MLKL (phosphorylation) in the rat myocardial tissues, Detection of RIPK1/RIPK3 necrosome complex formation,Higher RIPK3 level caused activation of CAMKII as a results MPT opening and myocardial necroptosis [118,119,120,121,122]
Atherosclerosis OxLDL- or APOE-deficient mice model Higher RIPK3 activation and subsequent necroptosis induction atheroma macrophages leads to the local and systemic inflammation and atherosclerotic lesions [123,124]
Aortic
aneurysm
Elastase-induced AAA C57BL/6 mice model Increased RIPK1 and RIPK3 level in aneurysmal tissues promotes AAA progression via caused SMC necroptosis and vascular inflammation (lymphocytes infiltration and DAMPs release) [125,126]
Calcium phosphate-induced AAA C57BL/6 mice model GSK'074 treatment diminished AAA progression by impeding SMC necroptosis, necroinflammation (macrophages infiltration and cytokines secretion) and aortic expansion in aneurysm-prone aortae [127]
6 Autoimmune diseases Psoriasis Primary epidermal keratinocytes cultured cells; Aldara-/IMQ- induced psoriasis mice models Enhanced RIPK3 expression facilitates psoriatic inflammation by neutrophil-mediated cytokines/chemokines secretion,Elevated RIPK1/-3/MLKL expression, detection of their localization in all layers of epidermal skin cells confirmed by confocal microscopy. [128,129,130]
Rheumatoid arthritis (RA) Collagen-induced arthritis mice model Enhanced RIPK1/RIPK3/MLKL expression promotes NLRP3 inflammasome complex formation and cytokines secretion in the synovium joint tissue,IFN-γ diminished necroptosis-mediated RA progression by downregulation of MLKL expression [131,132]
7 Cancer disease Acute myeloid leukemia (AML) DA1-3b p210BCR-ABL leukemia murine cell line; DA1-3b/C3HeOuJ mouse model Reduced RIPK3 expression observed in clinical samples from human AML patients was independently associated with poor prognosis,RIPK3 downregulation suggest diminished necroptosis via p65/RelA cleavage and as results shift towards NF-κβ mediate cell survival in DA1-3b leukemia cells [133]
Chronic lymphocytic leukemia (CLL) Primary CLL cells from human CLL patients Lower expression of RIPK3 and CYLD reduced TNF-α/zVAD mediated necroptosis in CML cells [134]
Head and neck squamous cell carcinoma (HNSCC) Primary and metastatic cell lines and tissues from human HNSCC patients Enhanced genomic methylation of RIPK1 promoter caused reduced TLR3-mediated apoptosis/necroptosis with higher tumor cells migration in HNSCC metastatic cells,Loss of RIPK1 expression strongly linked with metastatic disease in a cohort of HNSCC patients [135]
Non-small cell lung cancer (NSCLC) Clinical samples from 253 and 394 NSCLC human patients Lower RIPK1/-3/MLKL expression was linked with poor prognosis in a NSCLC tissues associated with reduced
levels of necroptosis signaling,
Lower RIPK1 and PELI with higher p53 expression found to be linked with a worse OS of stage-I NSCLC patients
[136]
Ovarian cancer Clinical samples from 75 human ovarian cancer patients Low MLKL level was significantly linked with both reduced DFS and OS of patients with ovarian cancer, MLKL serves as a potential prognosis marker in ovarian cancer patients [137]
Colon cancer HT29, Colo205, HCT116, SW480 colon cancer cell lines; Colon cancer tissues samples from human colon cancer patients Reduce RIPK1 and RIPK3 expressions (due to hypoxia) resists cancer cells to chemotherapeutic agents-induced necroptotic cell death;
Poly I:C induces TLR3/RIP3-dependent necroptosis and tumor growth inhibition via induction of DC cells mediated anti-tumor activity in colon cancer tissues
[138]
Cervical cancer HPV18-positive HeLa and C4-I cervical carcinoma cell lines RIPK3-upregulation stimulates IL1-α secretion from Poly I:C-induced necroptotic cervical cancer cells leads to activation DC cells, selective activation of DC cells shows anti-tumor effects via producing cytotoxic cytokine IL-12 or activating CD8+ T-cells [139]
Melanoma DM733, DM598, DM738 and DM833 melanoma cell lines; A2058 cells injected NCr-nu/nu miceB16 mouse melanoma cell lines and B16 cells injected C57Bl/6 mice melanoma metastasis model Selective inhibition of CYLD expression and activation of JNK/AP-1 and β1-integrin signaling by Snail is critical to protects melanoma from necroptosis in melanocytes and nevus cells,
zVAD-fmk in combination with RT, CT, HT increased necroptosis in B16-F10 melanoma cells concomitantly with HMGB1 secretion and increase cytotoxic DCs as well as CD8+ T-cells infiltration around tumor microenvironment.
RIPK3 upregulation induces NK T-cells mediated anti-tumor responses via mitochondrial PGAMF-NFAT/Drp1 signaling activation in metastatic melanoma tumor cells;Increased RIPK1 expression positively linked with the higher metastatic rate and a poor prognosis in melanoma potentially due to NF-κβ-mediated pro-tumorigenic abilities
[140,141,142]
Glioblastoma Tissue samples from human glioblastoma patients Increased RIPK1 levels prevents p53 induction via augmenting mdm2 level and NF-κβ signaling activation to confers a poor prognosis in glioblastoma [143]
Lung cancer HBEC-2, HBEC-13 and BEAS-2B cell lines; Cigarette smoke/Benzo(a)pyrene-exposed mouse lung tumor model Higher RIPK1 expression promotes BPDE-induced malignant transformation of HBEC cells by catalase-mediated suppression of ROS overproduction as well as MAPKs signaling deactivation [144]
Breast cancer Clinical samples of human breast cancer patients; MDA-MB231, 4T1, MCF10A and MCF12A breast cancer cell lines; MDA-MB-231/4T1 xenografted Balb/C mice model Nearly 85% patients of breast cancer have reduced RIPK3 expression that was associated with a worse prognosis, Lower RIPK3 expression suggest by genomic methylation of transcription factor in its transcriptional sites in breast cancer cells;
Lower RIPK1/-3/MLKL expression found to be linked with reduced breast cancer tumorigenicity due to impairment of NF-κβ-mediated pro-tumor growth cytokines secretion
[142]
Pancreatic adenocarcinoma (PAC) Tissue samples from 80 human PAC patients; AsPC1, PANC1, and MIA PaCa-2 pancreatic cancer cell lines; KrasG12D PDEC/ FC1242 cells xenografted C57BL/6 mice Decreased MLKL expression was strongly correlated with cancer progression with diminished necroptosis, MLKL serves as a therapeutic targets in PAC cells,
RIPK1/-3 dependent necroptosis signaling promotes pancreatic tumorigenicity through enhancing CXCL1 and Mincle-induced adaptive immune suppression in tumor-infiltrating myeloid cells;
Higher RIPK3 and MLKL levels promotes the pancreatic cancer cells migration and invasion via the activation of CXCL5-CXCR2 axis
[145]