{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMixed lineage kinase domain‐like protein (MLKL) has emerged as the obligate downstream effector of necroptosis. In response to death‐receptor or pathogen‐induced signals, its activation is initiated by receptor‐interacting protein kinase 3 (RIPK3)–mediated phosphorylation at key serine/threonine residues, triggering structural reorganization and oligomerization. Once activated, MLKL dissociates from the necrosome and translocates to the plasma membrane, where it disrupts membrane integrity and executes cell death. These seminal studies established MLKL’s central role as the switch that commits cells to a regulated necrotic fate."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic analyses have revealed that MLKL comprises an N‐terminal executioner domain—often a four‐helix bundle capable of directly perturbing lipid membranes—and a C‐terminal pseudokinase domain that regulates its activation. In-depth structural studies and biochemical assays show that following RIPK3 phosphorylation, the auto–inhibitory conformation is released, enabling higher‐order oligomerization (including tetrameric and octameric assemblies), association with phosphatidylinositol phosphates and even formation of novel cation channels. Moreover, regulatory inputs from inositol phosphate metabolites, chaperones such as Hsp90, thiol oxidoreductases, and receptor tyrosine kinases further fine‐tune the conformational dynamics and membrane‐targeting ability of MLKL."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "20"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in executing necroptosis, activated MLKL mediates potent inflammatory responses. Its membrane disruption not only causes ionic imbalance and leakage of intracellular contents but also leads to the exposure of phosphatidylserine and the release of damage‐associated molecular patterns (DAMPs) that drive caspase‐independent interleukin‐1β maturation via inflammasome activation. Dysregulation of MLKL activity has been implicated in a broad spectrum of diseases—including inflammatory disorders, liver injury, various cancers (such as pancreatic, colon, and acute myeloid leukemia), atherosclerosis, and even pneumonia—underscoring its potential as both a biomarker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "36"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to driving necroptotic cell death, emerging evidence points to novel non‐necrotic roles for MLKL. Recent work suggests that MLKL can regulate endosomal trafficking, receptor degradation, and extracellular vesicle generation, thus modulating the intensity and character of immune responses. Advances in structural biology and the development of specific inhibitors—ranging from small molecules targeting RIPK3/MLKL interactions to compounds that modulate upstream regulators such as PI3K, TAM kinases, and Hsp90—are opening promising therapeutic avenues in the management of inflammatory and neoplastic diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "48"}]}, {"type": "t", "text": "\n"}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Liming Sun, Huayi Wang, Zhigao Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase."}]}, {"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.2011.11.031"}], "href": "https://doi.org/10.1016/j.cell.2011.11.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22265413"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22265413"}]}, {"type": "r", "ref": 2, "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": 3, "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": 4, "children": [{"type": "t", "text": "Zhenyu Cai, Siriporn Jitkaew, Jie Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb2883"}], "href": "https://doi.org/10.1038/ncb2883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24316671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24316671"}]}, {"type": "r", "ref": 5, "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": 6, "children": [{"type": "t", "text": "Yves Dondelinger, Wim Declercq, Sylvie Montessuit, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2014.04.026"}], "href": "https://doi.org/10.1016/j.celrep.2014.04.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24813885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24813885"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lijing Su, Bradley Quade, Huayi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A plug release mechanism for membrane permeation by MLKL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2014.07.014"}], "href": "https://doi.org/10.1016/j.str.2014.07.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25220470"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25220470"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "James M Murphy, Isabelle S Lucet, Joanne M Hildebrand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20131270"}], "href": "https://doi.org/10.1042/BJ20131270"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24219132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24219132"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Diep-Khanh Ho Vo, Yasuomi Urano, Wakako Takabe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "24(S)-Hydroxycholesterol induces RIPK1-dependent but MLKL-independent cell death in the absence of caspase-8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Steroids (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.steroids.2015.02.007"}], "href": "https://doi.org/10.1016/j.steroids.2015.02.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25697054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25697054"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Sue Kyung Kim, Woo-Jung Kim, Jung-Ho Yoon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulated RIP3 Expression Potentiates MLKL Phosphorylation-Mediated Programmed Necrosis in Toxic Epidermal Necrolysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2015.90"}], "href": "https://doi.org/10.1038/jid.2015.90"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25748555"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25748555"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Maria C Tanzer, Anne Tripaydonis, Andrew I Webb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Necroptosis signalling is tuned by phosphorylation of MLKL residues outside the pseudokinase domain activation loop."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20150678"}], "href": "https://doi.org/10.1042/BJ20150678"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26283547"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26283547"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Giovanni Quarato, Cliff S Guy, Christy R Grace, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2016.01.011"}], "href": "https://doi.org/10.1016/j.molcel.2016.01.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26853145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26853145"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "M C Tanzer, I Matti, J M Hildebrand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evolutionary divergence of the necroptosis effector MLKL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2015.169"}], "href": "https://doi.org/10.1038/cdd.2015.169"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26868910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26868910"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Bingqing Xia, Sui Fang, Xueqin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLKL forms cation channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2016.26"}], "href": "https://doi.org/10.1038/cr.2016.26"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27033670"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27033670"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Deli Huang, Xinru Zheng, Zi-An Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The MLKL Channel in Necroptosis Is an Octamer Formed by Tetramers in a Dyadic Process."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00497-16"}], "href": "https://doi.org/10.1128/MCB.00497-16"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27920255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27920255"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Amit Gaba, Fang Xu, Yao Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The NS1 Protein of Influenza A Virus Participates in Necroptosis by Interacting with MLKL and Increasing Its Oligomerization and Membrane Translocation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.01835-18"}], "href": "https://doi.org/10.1128/JVI.01835-18"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30355688"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30355688"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Dan E McNamara, Cole M Dovey, Andrew T Hale, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Chem Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chembiol.2019.03.010"}], "href": "https://doi.org/10.1016/j.chembiol.2019.03.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31031142"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31031142"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Ayaz Najafov, Adnan K Mookhtiar, Hoang Son Luu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2019.05.022"}], "href": "https://doi.org/10.1016/j.molcel.2019.05.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31230815"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31230815"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Sarah E Garnish, Yanxiang Meng, Akiko Koide, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-22400-z"}], "href": "https://doi.org/10.1038/s41467-021-22400-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33850121"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33850121"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Yanxiang Meng, Katherine A Davies, Cheree Fitzgibbon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-27032-x"}], "href": "https://doi.org/10.1038/s41467-021-27032-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34811356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34811356"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Lauren E Colbert, Sarah B Fisher, Claire W Hardy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cncr.28144"}], "href": "https://doi.org/10.1002/cncr.28144"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23720157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23720157"}]}, {"type": "r", "ref": 22, "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": 23, "children": [{"type": "t", "text": "J Blohberger, L Kunz, D Einwang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2015.51"}], "href": "https://doi.org/10.1038/cddis.2015.51"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25766324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25766324"}]}, {"type": "r", "ref": 24, "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": 25, "children": [{"type": "t", "text": "X M Zhao, Z Chen, J B Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2015.390"}], "href": "https://doi.org/10.1038/cddis.2015.390"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26866270"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26866270"}]}, {"type": "r", "ref": 26, "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": 27, "children": [{"type": "t", "text": "Xian Li, Jing Guo, Ai-Ping Ding, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of Mixed Lineage Kinase Domain-Like Protein Expression With Prognosis in Patients With Colon Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Technol Cancer Res Treat (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1533034616655909"}], "href": "https://doi.org/10.1177/1533034616655909"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27432118"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27432118"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Claudia Günther, Gui-Wei He, Andreas E Kremer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI87545"}], "href": "https://doi.org/10.1172/JCI87545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27756058"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27756058"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Kimberley D Gutierrez, Michael A Davis, Brian P Daniels, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1601757"}], "href": "https://doi.org/10.4049/jimmunol.1601757"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28130493"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28130493"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Sefi Zargarian, Inbar Shlomovitz, Ziv Erlich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphatidylserine externalization, \"necroptotic bodies\" release, and phagocytosis during necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.2002711"}], "href": "https://doi.org/10.1371/journal.pbio.2002711"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28650960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28650960"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Eduardo Reynoso, Hua Liu, Lin Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thioredoxin-1 actively maintains the pseudokinase MLKL in a reduced state to suppress disulfide bond-dependent MLKL polymer formation and necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M117.799353"}], "href": "https://doi.org/10.1074/jbc.M117.799353"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28878015"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28878015"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Lin Jing, Fei Song, Zhenyu Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLKL-PITPα signaling-mediated necroptosis contributes to cisplatin-triggered cell death in lung cancer A549 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2017.10.047"}], "href": "https://doi.org/10.1016/j.canlet.2017.10.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29104146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29104146"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Hui Chen, Yulu Fang, Jianfeng Wu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Necroptosis-driving genes "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "RIPK1, RIPK3"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " and "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MLKL-p"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " are associated with intratumoral CD3"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " and CD8"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " T cell density and predict prognosis in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunother Cancer (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jitc-2021-004031"}], "href": "https://doi.org/10.1136/jitc-2021-004031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35264437"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35264437"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Jiaying Ruan, Ling Mei, Qian Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixed lineage kinase domain-like protein is a prognostic biomarker for cervical squamous cell cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26823841"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26823841"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Susanne Radonjic-Hoesli, Xiaoliang Wang, Elisabeth de Graauw, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Biological events and molecular signaling following MLKL activation during necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384101.2017.1371889"}], "href": "https://doi.org/10.1080/15384101.2017.1371889"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28854080"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28854080"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Emma J Petrie, Jarrod J Sandow, Annette V Jacobsen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Current translational potential and underlying molecular mechanisms of necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-2094-z"}], "href": "https://doi.org/10.1038/s41419-019-2094-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31719524"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31719524"}]}, {"type": "r", "ref": 45, "children": [{"type": "t", "text": "Shiping Hu, Xixi Chang, Hongbin Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cytokine (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cyto.2020.155046"}], "href": "https://doi.org/10.1016/j.cyto.2020.155046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32114297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32114297"}]}, {"type": "r", "ref": 46, "children": [{"type": "t", "text": "André L Samson, Sarah E Garnish, Joanne M Hildebrand, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MLKL: Functions beyond serving as the Executioner of Necroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Theranostics (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/thno.54072"}], "href": "https://doi.org/10.7150/thno.54072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33754026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33754026"}]}]}]}