{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRIPK3 is a master regulator of programmed necrosis (necroptosis) that is activated by death‐receptor stimuli such as tumor necrosis factor‐α. Once triggered, RIPK3 interacts with RIPK1 via RHIM domains to assemble an amyloid‐like “necrosome” complex, which in turn recruits and phosphorylates the pseudokinase MLKL. This phosphorylation event promotes MLKL oligomerization, its translocation to cellular membranes, and ultimately disruption of membrane integrity through phospholipid binding—a cascade essential for necroptosis execution. Moreover, RIPK3 activity is further modulated by reactive oxygen species that amplify its signaling, and viral pathogens may target its pathway to subvert host cell death responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in necroptosis, RIPK3 helps determine cell fate by modulating the balance between necroptotic and apoptotic pathways. Structural studies reveal that conformational changes in RIPK3—such as those governing its interaction with MLKL—are critical for switching between cell death modalities. In some contexts, kinase‐inactivating mutations can unexpectedly trigger apoptosis via alternative complex formation, underscoring a sophisticated regulation of cell death decisions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRIPK3 activity is also intricately linked to inflammatory and immune responses. Activation of RIPK3 not only drives necroptotic cell death but also leads to the release of damage‐associated molecular patterns and pro‐inflammatory cytokines. In diverse disease settings—including non‐alcoholic steatohepatitis, inflammatory bowel disorders, acute vascular injury, and cerebral ischemia—RIPK3‐dependent signaling amplifies inflammation, promotes tissue remodeling, and shapes the local immune microenvironment. Furthermore, its role in modulating myeloid cell metabolism and suppressing tumor‐promoting pathways highlights its impact on both tissue injury and cancer development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPost‐translational mechanisms are crucial for fine‐tuning RIPK3 activity. Its levels are tightly controlled through ubiquitination and proteasomal degradation—processes mediated by E3 ligases such as PELI1—which prevent deleterious overactivation. Conversely, disruptions in proteasome function (for example, due to chronic alcohol exposure) can lead to aberrant RIPK3 accumulation. In parallel, RIPK3 orchestrates metabolic reprogramming by directly phosphorylating components of the pyruvate dehydrogenase complex and enhancing mitochondrial respiration, which increases reactive oxygen species production and sensitizes cells to necroptosis. Additionally, compounds such as shikonin leverage RIPK3‐dependent ROS generation to trigger necroptosis in cancer cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, aberrant RIPK3 expression and activity have been linked to a range of pathological states. In certain cancers, epigenetic silencing of RIPK3 is associated with resistance to chemotherapeutic agents, whereas restoration of its expression can re‐sensitize tumor cells to cell death and enhance antitumor immunity. Similarly, in inflammatory and fibrotic diseases such as renal fibrosis, vascular aneurysm progression, and colorectal cancer, dysregulated RIPK3 signaling contributes to disease severity, making it an attractive target for novel therapeutic interventions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sudan He, Lai Wang, Lin Miao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2009.05.021"}], "href": "https://doi.org/10.1016/j.cell.2009.05.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19524512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19524512"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Huayi Wang, Liming Sun, Lijing Su, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2014.03.003"}], "href": "https://doi.org/10.1016/j.molcel.2014.03.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24703947"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24703947"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jixi Li, Thomas McQuade, Ansgar B Siemer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2012.06.019"}], "href": "https://doi.org/10.1016/j.cell.2012.06.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22817896"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22817896"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jie Zhao, Siriporn Jitkaew, Zhenyu Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1200012109"}], "href": "https://doi.org/10.1073/pnas.1200012109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22421439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22421439"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Pratyusha Mandal, Scott B Berger, Sirika Pillay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIP3 induces apoptosis independent of pronecrotic kinase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2014.10.021"}], "href": "https://doi.org/10.1016/j.molcel.2014.10.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25459880"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25459880"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yingying Zhang, Sheng Sean Su, Shubo Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms14329"}], "href": "https://doi.org/10.1038/ncomms14329"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28176780"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28176780"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Peter Vandenabeele, Wim Declercq, Franky Van Herreweghe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of the kinases RIP1 and RIP3 in TNF-induced necrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.3115re4"}], "href": "https://doi.org/10.1126/scisignal.3115re4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20354226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20354226"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Gi-Bang Koo, Michael J Morgan, Da-Gyum Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2015.56"}], "href": "https://doi.org/10.1038/cr.2015.56"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25952668"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25952668"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kim Newton, Gerard Manning "}, {"type": "b", "children": [{"type": "t", "text": "Necroptosis and Inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Annu Rev Biochem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1146/annurev-biochem-060815-014830"}], "href": "https://doi.org/10.1146/annurev-biochem-060815-014830"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26865533"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26865533"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Wanze Chen, Zhenru Zhou, Lisheng Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.435545"}], "href": "https://doi.org/10.1074/jbc.M112.435545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23612963"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23612963"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Hongyan Guo, Shinya Omoto, Philip A Harris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Herpes simplex virus suppresses necroptosis in human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2015.01.003"}], "href": "https://doi.org/10.1016/j.chom.2015.01.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25674983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25674983"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Zhentao Yang, Yan Wang, Yingying Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41556-017-0022-y"}], "href": "https://doi.org/10.1038/s41556-017-0022-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29358703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29358703"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Tian Xie, Wei Peng, Chuangye Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into RIP3-mediated necroptotic signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2013.08.044"}], "href": "https://doi.org/10.1016/j.celrep.2013.08.044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24095729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24095729"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jinho Seo, Eun-Woo Lee, Hyerim Sung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb3314"}], "href": "https://doi.org/10.1038/ncb3314"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26900751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26900751"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Xiaqiong Wang, Wei Jiang, Yiqing Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3015"}], "href": "https://doi.org/10.1038/ni.3015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25326752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25326752"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jérémie Gautheron, Mihael Vucur, Florian Reisinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Mol Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/emmm.201403856"}], "href": "https://doi.org/10.15252/emmm.201403856"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24963148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24963148"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Maria Pierdomenico, Anna Negroni, Laura Stronati, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Gastroenterol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ajg.2013.403"}], "href": "https://doi.org/10.1038/ajg.2013.403"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24322838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24322838"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Ulrike Höckendorf, Monica Yabal, Tobias Herold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2016.06.002"}], "href": "https://doi.org/10.1016/j.ccell.2016.06.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27411587"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27411587"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Lei Wu, Xiao Zhang, Lu Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Immunol Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2326-6066.CIR-19-0261"}], "href": "https://doi.org/10.1158/2326-6066.CIR-19-0261"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32122992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32122992"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Angara Sureshbabu, Edwin Patino, Kevin C Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.98411"}], "href": "https://doi.org/10.1172/jci.insight.98411"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29875323"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29875323"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "M Vieira, J Fernandes, L Carreto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ischemic insults induce necroptotic cell death in hippocampal neurons through the up-regulation of endogenous RIP3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Dis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nbd.2014.04.002"}], "href": "https://doi.org/10.1016/j.nbd.2014.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24746856"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24746856"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Hui Chen, Yulu Fang, Jianfeng Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-018-0936-8"}], "href": "https://doi.org/10.1038/s41419-018-0936-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30158627"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30158627"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Qiwei Wang, Zhenjie Liu, Jun Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.116.304899"}], "href": "https://doi.org/10.1161/CIRCRESAHA.116.304899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25563840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25563840"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Guifang Yan, Huakan Zhao, Qi Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A RIPK3-PGE"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "2"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-17-3962"}], "href": "https://doi.org/10.1158/0008-5472.CAN-17-3962"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30012671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30012671"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Nieves Peltzer, Henning Walczak "}, {"type": "b", "children": [{"type": "t", "text": "Cell Death and Inflammation - A Vital but Dangerous Liaison."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.it.2019.03.006"}], "href": "https://doi.org/10.1016/j.it.2019.03.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31003931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31003931"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Zeze Fu, Biyong Deng, Yuxin Liao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-13-580"}], "href": "https://doi.org/10.1186/1471-2407-13-580"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24314238"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24314238"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Bin Lu, Xu Gong, Zong-Qi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Pharmacol Sin (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/aps.2017.112"}], "href": "https://doi.org/10.1038/aps.2017.112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28816233"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28816233"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Shaogui Wang, Hong-Min Ni, Kenneth Dorko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.6893"}], "href": "https://doi.org/10.18632/oncotarget.6893"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26769846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26769846"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Seung-Won Choi, Han-Hee Park, Soyeon Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.05.016"}], "href": "https://doi.org/10.1016/j.molcel.2018.05.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29883609"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29883609"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Xinfang Yu, Qipan Deng, Wei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neoalbaconol induces cell death through necroptosis by regulating RIPK-dependent autocrine TNFα and ROS production."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.3038"}], "href": "https://doi.org/10.18632/oncotarget.3038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25575821"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25575821"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Susanne V Schmidt, Stefanie Seibert, Barbara Walch-Rückheim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.3249"}], "href": "https://doi.org/10.18632/oncotarget.3249"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25888634"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25888634"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Mitsuru Imamura, Jong-Seok Moon, Kuei-Pin Chung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.94979"}], "href": "https://doi.org/10.1172/jci.insight.94979"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29415885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29415885"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Han-Hee Park, Hwa-Ryeon Kim, Sang-Yeong Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12943-021-01399-3"}], "href": "https://doi.org/10.1186/s12943-021-01399-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34419074"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34419074"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Jérémie Gautheron, Mihael Vucur, Anne T Schneider, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms11869"}], "href": "https://doi.org/10.1038/ncomms11869"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27323669"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27323669"}]}]}]}