{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:36:14Z","timestamp":1788780974161,"version":"build-2803163510"},"reference-count":98,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, due to the limited efficacy of current therapeutic strategies in advanced stages. Necroptosis, a regulated form of necrotic cell death mediated by receptor-interacting protein kinases RIPK1 and RIPK3, and the pseudokinase MLKL, has emerged as a potential alternative pathway to induce cancer cell death. Recent studies suggest that modulation of necroptosis may enhance antitumor immunity, overcome therapeutic resistance, and improve clinical outcomes in CRC. In this review, we systematically analyzed the current literature on the role of necroptosis in CRC, focusing on molecular mechanisms, experimental models, and therapeutic implications. By critically evaluating the available evidence, we aimed to determine whether targeting RIPK1, RIPK3, and MLKL, or other novel agents, represents a promising horizon or a blind alley in the development of novel CRC therapies.<\/jats:p>","DOI":"10.3390\/ijms262211101","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T10:24:58Z","timestamp":1763375098000},"page":"11101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Trigger Points of Necroptosis (RIPK1, RIPK3, and MLKL)\u2014Promising Horizon or Blind Alley in Therapy of Colorectal Cancer?"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9957-5988","authenticated-orcid":false,"given":"Marcin","family":"Soko\u0142owski","sequence":"first","affiliation":[{"name":"Dr Alfred Soko\u0142owski Specialist Hospital in Walbrzych, 58-309 Walbrzych, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8199-2018","authenticated-orcid":false,"given":"Aleksandra","family":"Butrym","sequence":"additional","affiliation":[{"name":"Dr Alfred Soko\u0142owski Specialist Hospital in Walbrzych, 58-309 Walbrzych, Poland"},{"name":"Department of Hematology and Oncology, Wroclaw Medical University, Branch in Walbrzych, 50-556 Wroclaw, Poland"},{"name":"Oncology Clinical Trial Support Center, Alfred Sokolowski Specialistic Hospital in Walbrzych, 58-309 Walbrzych, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"ref_1","first-page":"233","article-title":"Colorectal cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"998","DOI":"10.2174\/18735592MTEx9NTk2y","article-title":"Colorectal cancer epidemiology: Recent trends and impact on outcomes","volume":"22","author":"Baidoun","year":"2021","journal-title":"Curr. Drug Targets"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1056\/NEJMoa033025","article-title":"Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractorymetastatic colorectal cancer","volume":"351","author":"Cunningham","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4706","DOI":"10.1200\/JCO.2009.27.6055","article-title":"Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer","volume":"28","author":"Peeters","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1200\/JCO.2012.42.8201","article-title":"Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen","volume":"30","author":"Tabernero","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1200\/JCO.2006.09.6305","article-title":"Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200","volume":"25","author":"Giantonio","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/S1470-2045(14)70330-4","article-title":"FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial","volume":"15","author":"Heinemann","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(12)61900-X","article-title":"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial","volume":"381","author":"Grothey","year":"2013","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1056\/NEJMoa1414325","article-title":"Randomized trial of TAS-102 for refractory metastatic colorectal cancer","volume":"372","author":"Mayer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Shiu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.annonc.2022.06.008","article-title":"Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142","volume":"33","author":"Lonardi","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1056\/NEJMoa2402141","article-title":"Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer","volume":"391","author":"Andre","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhu, T., and Wu, B.W. (2024). Recognition of necroptosis: From molecular mechanisms to detection methods. Biomed. Pharmacother., 178.","DOI":"10.1016\/j.biopha.2024.117196"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104439","DOI":"10.1016\/j.phrs.2019.104439","article-title":"Necroptosis signaling in liver diseases: An update","volume":"148","author":"Saeed","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.chembiol.2020.03.016","article-title":"Ferroptosis and Necroptosis in the Kidney","volume":"27","author":"Belavgeni","year":"2020","journal-title":"Cell Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2905","DOI":"10.1038\/cddis.2017.286","article-title":"Necroptosis in neurodegenerative diseases: A potential therapeutic target","volume":"8","author":"Zhang","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.yjmcc.2022.05.006","article-title":"Necroptosis in heart disease: Molecular mechanisms and therapeutic implications","volume":"169","author":"Guo","year":"2022","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41419-023-05841-w","article-title":"RIPK1-dependent necroptosis promotes vasculogenic mimicry formation via eIF4E in triple-negative breast cancer","volume":"14","author":"Li","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Soko\u0142owski, M., \u0141acina, P., Bogunia-Kubik, K., Mazur, G., and Butrym, A. (2025). Polymorphisms in Necroptosis Pathway Genes: Novel Prognostic Markers for Multiple Myeloma Treatment Outcomes. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115237"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5503","DOI":"10.7150\/jca.46172","article-title":"Expression of key regulatory genes in necroptosis and its effect on the prognosis in non-small cell lung cancer","volume":"11","author":"Park","year":"2020","journal-title":"J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.4049\/jimmunol.141.8.2629","article-title":"Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis","volume":"141","author":"Laster","year":"1988","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1084\/jem.187.9.1477","article-title":"Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor","volume":"187","author":"Vercammen","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1083\/jcb.143.5.1353","article-title":"Caspase-independent cell killing by Fas-associatedprotein with death domain","volume":"143","author":"Kawahara","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/82732","article-title":"Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule","volume":"1","author":"Holler","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"51613","DOI":"10.1074\/jbc.M305633200","article-title":"A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses","volume":"278","author":"Chan","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nchembio.83","article-title":"Identification of RIP1 kinase as a specific cellular target of necrostatins","volume":"4","author":"Degterev","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.cell.2009.05.021","article-title":"Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha","volume":"137","author":"He","year":"2009","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","article-title":"Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase","volume":"148","author":"Sun","year":"2012","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/cdd.2011.96","article-title":"Molecular definitions of cell death subroutines: Recommendations of the Nomenclature Committee on Cell Death 2012","volume":"19","author":"Galluzzi","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31268","DOI":"10.1074\/jbc.M113.462341","article-title":"Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL","volume":"288","author":"Kaiser","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/nrm2970","article-title":"Molecular mechanisms of necroptosis: An ordered cellular explosion","volume":"11","author":"Vandenabeele","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.molcel.2006.03.026","article-title":"Activation of IKK by TNF\u03b1 requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO","volume":"22","author":"Ea","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0092-8674(03)00521-X","article-title":"Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes","volume":"114","author":"Micheau","year":"2003","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.tips.2016.12.005","article-title":"Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis","volume":"38","author":"Wegner","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.molcel.2018.01.027","article-title":"Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2","volume":"69","author":"Annibaldi","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1038\/cdd.2014.77","article-title":"Distinct roles of RIP1-RIP3 hetero- and RIP3-RIP3 homo-interaction in mediating necroptosis","volume":"21","author":"Wu","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/imr.12541","article-title":"Caspase-8: Regulating life and death","volume":"277","author":"Tummers","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","article-title":"Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis","volume":"575","author":"Fritsch","year":"2019","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.yexcr.2019.04.027","article-title":"Pan-caspase inhibitors induce necroptosis via ROS-mediated activation of mixed lineage kinase domain-like protein and p38 in classically activated macrophages","volume":"380","author":"Koike","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1158\/0008-5472.CAN-08-2256","article-title":"cIAP1, cIAP2, and XIAP act cooperatively via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation","volume":"69","author":"Jin","year":"2009","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.cell.2008.10.044","article-title":"Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway","volume":"135","author":"Hitomi","year":"2008","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Moquin, D.M., and McQuade, T. (2013). CYLD deubiquitinates RIP1 in the TNF\u03b1-induced necrosome to facilitate kinase activation and programmed necrosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076841"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/ncb2362","article-title":"Caspase 8 inhibits programmed necrosis by processing CYLD","volume":"13","author":"Donnell","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1073\/pnas.1505244112","article-title":"A cytosolic heat shock protein 90 and cochaperone CDC37 complex is required for RIP3 activation during necroptosis","volume":"112","author":"Li","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.cell.2012.06.019","article-title":"The RIP1\/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis","volume":"150","author":"Li","year":"2012","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/cdd.2015.70","article-title":"Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL duringnecroptosis","volume":"23","author":"Rodriguez","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/ncb3120","article-title":"Ppm1b negatively regulates necroptosis through dephosphorylating Rip3","volume":"17","author":"Chen","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1007\/s10495-016-1303-9","article-title":"Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation","volume":"12","author":"Raninga","year":"2016","journal-title":"Apoptosis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.immuni.2013.06.018","article-title":"The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism","volume":"39","author":"Murphy","year":"2013","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.molcel.2016.01.011","article-title":"Sequential engagement of distinct MLKL phosphatidylinositol-binding sites executes necroptosis","volume":"61","author":"Quarato","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ncb2883","article-title":"Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis","volume":"16","author":"Cai","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3892\/ijo.2014.2804","article-title":"Shikonin dually functions as a proteasome inhibitor and a necroptosis inducer in multiple myeloma cells","volume":"46","author":"Wada","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Lu, W., and Sun, J. (2016). Mitochondrial protein PGAM5 regulates mitophagic protection against cell necroptosis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147792"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.immuni.2013.02.003","article-title":"Necroptosis: The Release of Damage-Associated Molecular Patterns and Its Physiological Relevance","volume":"38","author":"Kaczmarek","year":"2013","journal-title":"Immunity"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Guerrache, A., and Micheau, O. (2024). TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling. Cells, 13.","DOI":"10.3390\/cells13060521"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.immuni.2016.06.007","article-title":"RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4","volume":"45","author":"Najjar","year":"2016","journal-title":"Immunity"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.cell.2020.02.050","article-title":"Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis","volume":"180","author":"Zhang","year":"2020","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41586-020-2129-8","article-title":"Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation","volume":"580","author":"Jiao","year":"2020","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"E3109","DOI":"10.1073\/pnas.1301218110","article-title":"Interferon-induced RIP1\/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases","volume":"110","author":"Thapa","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41423-019-0237-x","article-title":"ZBP1 mediates interferon-inducednecroptosis","volume":"17","author":"Yang","year":"2020","journal-title":"Cell Mol. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Lin, Y. (2014). RIP1-Mediated Signaling Pathways in Cell Survival and Death Control. Necrotic Cell Death, Springer.","DOI":"10.1007\/978-1-4614-8220-8_2"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/0092-8674(95)90072-1","article-title":"RIP: A novel protein containing a death domain that interacts withFas\/APO-1 (CD95) in yeast and causes cell death","volume":"81","author":"Stanger","year":"1995","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/s41580-023-00623-w","article-title":"Roles of RIPK1 as a stress sentinel coordinating cell survival and immunogenic cell death","volume":"24","author":"Clucas","year":"2023","journal-title":"Nat. Rev. Mol.Cell Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/cdd.2012.151","article-title":"Necrostatin-1 blocks both RIPK1 and IDO: Consequences for the studyof cell death in experimental disease models","volume":"20","author":"Vandenabeele","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41419-024-07325-x","article-title":"TRAF2 and RIPK1 redundantly mediate classical NF\u03baB signaling by TNFR1 and CD95-type death receptors","volume":"16","author":"Wagner","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/j.immuni.2024.04.016","article-title":"The RIPK1 deathdomain restrains ZBP1- and TRIF-mediated cell death and inflammation","volume":"57","author":"Imai","year":"2024","journal-title":"Immunity"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/j.cub.2007.07.041","article-title":"Optineurin negatively regulates TNF\u03b1-induced NF-\u03baB activation by competing with NEMO for ubiquitinated RIP","volume":"17","author":"Zhu","year":"2007","journal-title":"Curr. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/imr.12550","article-title":"The interplay of IKK, NF-\u03baB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation","volume":"277","author":"Kondylis","year":"2017","journal-title":"Immunol Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1158\/0008-5472.CAN-17-3082","article-title":"RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca2\u207a Uptake and Promotes Colorectal Oncogenesis","volume":"78","author":"Zeng","year":"2018","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.jcmgh.2020.10.009","article-title":"The Fragile X Mental Retardation Protein Regulates RIPK1 and Colorectal Cancer Resistance to Necroptosis","volume":"11","author":"Marafini","year":"2021","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41419-022-05524-y","article-title":"TRAF6 regulates the abundance of RIPK1 and inhibits the RIPK1\/RIPK3\/MLKL necroptosis signaling pathway and affects the progression of colorectal cancer","volume":"14","author":"Lin","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/s41417-023-00647-6","article-title":"A novel RIP1-mediated canonical WNT signaling pathway that promotes colorectal cancer metastasis via \u03b2 -catenin stabilization-induced EMT","volume":"30","author":"Kang","year":"2023","journal-title":"Cancer Gene Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41420-024-01957-w","article-title":"RIPK3 signaling and its role in regulated cell death and diseases","volume":"10","author":"Zhou","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"E31","DOI":"10.25011\/cim.v42i1.32390","article-title":"RIPK3 expression as a potential predictive and prognostic marker in metastatic colon cancer","volume":"42","author":"Conev","year":"2019","journal-title":"Clin. Investig. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1084\/jem.20160442","article-title":"Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice","volume":"214","author":"He","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"46384","DOI":"10.18632\/oncotarget.10135","article-title":"Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis","volume":"7","author":"Bozec","year":"2016","journal-title":"Oncotarget"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.7150\/thno.32126","article-title":"RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression","volume":"9","author":"Liu","year":"2019","journal-title":"Theranostics"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e09277","DOI":"10.1002\/advs.202509277","article-title":"Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities","volume":"12","author":"Xu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.canlet.2019.05.034","article-title":"MLKL attenuates colon inflammation and colitis-tumorigenesis via suppression of inflammatory responses","volume":"459","author":"Zhao","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1177\/1533034616655909","article-title":"Association of Mixed Lineage Kinase Domain-Like Protein Expression with Prognosis in Patients with Colon Cancer","volume":"16","author":"Li","year":"2017","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"O\u2019Connell, E., Reynolds, I.S., Lindner, A.U., Salvucci, M., O\u2019Grady, T., Bacon, O., Cho, S., McDonough, E., Longley, D., and Ginty, F. (2022). Apoptotic and Necroptotic Mediators are Differentially Expressed in Mucinous and Non-Mucinous Colorectal Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.815001"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1038\/s41467-018-05979-8","article-title":"Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes","volume":"9","author":"Roose","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_84","first-page":"3174","article-title":"Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice","volume":"5","author":"Liu","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.bbalip.2018.11.002","article-title":"Upregulation of human glycolipid transfer protein (GLTP) induces necroptosis in colon carcinoma cells","volume":"1864","author":"Mishra","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/s41419-023-05752-w","article-title":"PRMT1 reverts the immune escape of necroptotic colon cancer through RIP3 methylation","volume":"14","author":"Zhang","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Tan, L., Wang, S., Chang, W., Zhang, X., Deng, R., Yan, H., Zhu, W., Wang, H., Cai, Y., and Liu, Z. (2025). Role of necroptosis-related genes in immune activity and prognosis of colorectal cancer. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1619749"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1039\/C7FO01040K","article-title":"Cationic peroxidase from proso millet induces human colon cancer cell necroptosis by regulating autocrine TNF-\u03b1 and RIPK3 demethylation","volume":"9","author":"Cui","year":"2018","journal-title":"Food Funct."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/1873-3468.14310","article-title":"Diet-derived ergothioneine induces necroptosis in colorectal cancer cells by activating the SIRT3\/MLKL pathway","volume":"596","author":"Onofrio","year":"2022","journal-title":"FEBS Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.freeradbiomed.2017.04.010","article-title":"Cytosolic calcium mediates RIP1\/RIP3 complex-dependent necroptosis through JNK activation and mitochondrial ROS production in human colon cancer cells","volume":"108","author":"Sun","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.7314\/APJCP.2015.16.6.2569","article-title":"Cobalt chloride induces necroptosis in human colon cancer HT-29 cells","volume":"16","author":"Wang","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3399","DOI":"10.1038\/onc.2015.398","article-title":"Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-\u03b1-dependent necroptosis driven by RIP1 kinase and NF-\u03baB","volume":"35","author":"Metzig","year":"2016","journal-title":"Oncogene"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Grassilli, E., Ianzano, L., Bonomo, S., Missaglia, C., Cerrito, M.G., Giovannoni, R., Masiero, L., and Lavitrano, M. (2014). GSK3A isredundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100947"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.biomaterials.2016.12.032","article-title":"Killing colon cancer cells through PCD pathways by a novel hyaluronic acid-modified shell-core nanoparticle loaded with RIP3 in combination with chloroquine","volume":"124","author":"Hou","year":"2017","journal-title":"Biomaterials"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Wu, Y., Xu, Y., Chen, Y., Xu, W., Yao, M., and Ding, W. (2025). Development of a prognostic prediction model based on damage-associated molecular pattern for colorectal cancer applying bulk RNA-seq analysis. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-10592-z"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41698-023-00488-4","article-title":"Profiling the heterogeneity of colorectal cancer consensus molecular subtypes using spatial transcriptomics","volume":"8","author":"Valdeolivas","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Xu, H., Cui, H., Weng, S., Zhang, Y., Wang, L., Xing, Z., Han, X., and Liu, Z. (2024). Crosstalk of cell death pathways unveils an autophagy-related gene AOC3 as a critical prognostic marker in colorectal cancer. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-05980-6"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/cddis.2015.16","article-title":"Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death","volume":"6","author":"Moriwaki","year":"2015","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T10:35:15Z","timestamp":1763375715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":98,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211101"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211101","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]}}}