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| Open AccessPolyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer
Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models.
- Guoshu Bi
- , Jiaqi Liang
- & Cheng Zhan
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Article
| Open AccessInhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis
Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.
- Naoya Yamada
- , Tadayoshi Karasawa
- & Masafumi Takahashi
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Article
| Open AccessPCDHA9 as a candidate gene for amyotrophic lateral sclerosis
Genetic mutations are found in only 15% of sporadic ALS. Here, authors identify PCDHA9 as a candidate ALS gene and elucidate detailed underlying pathogenesis using mice with Pcdhα9 mutations that develop typical ALS phenotype and hallmark pathology.
- Jie Zhong
- , Chaodong Wang
- & Zhiheng Xu
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Article
| Open AccessCell-lysis sensing drives biofilm formation in Vibrio cholerae
Bacteria form matrix-encapsulated communities, called biofilms, which protect resident cells from environmental challenges. Here, the authors show that Vibrio cholerae cells detect environmental threats by sensing a cellular component released through kin cell lysis, which induces formation of biofilms by surviving cells.
- Jojo A. Prentice
- , Robert van de Weerd
- & Andrew A. Bridges
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Article
| Open AccessPro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
Ferroptosis is a novel form of regulated cell death associated with lipid oxidation. Here, the authors demonstrate that the proferroptosis signal is activated and drives vascular aging by inducing senescence in vascular smooth muscle cells.
- Di-Yang Sun
- , Wen-Bin Wu
- & Pei Wang
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Article
| Open AccessMolecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy
The balance between apoptosis and autophagy is critical for normal development, proper tissue function, and disease pathogenesis. Here, the authors show previously unannotated BIRC6 domains, including a ubiquitin-like domain, and how it utilizes its ubiquitylation function to regulate both apoptosis and autophagy.
- Shuo-Shuo Liu
- , Tian-Xia Jiang
- & Xiao-Bo Qiu
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Article
| Open AccessMitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging
Dysregulated autophagy and mitochondrial function are two well-described hallmarks of aging. Here, the authors describe an unexpected age-associated upregulation of mitophagy in response to neuroinflammation triggered by leaked mtDNA.
- Juan Ignacio Jiménez-Loygorri
- , Beatriz Villarejo-Zori
- & Patricia Boya
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Article
| Open AccessApoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis
Mucins on the surface of healthy T cells limit their phagocytic uptake by macrophages. Here the authors show that upon apoptosis induction in T cells, surface mucins are cleaved and released by ADAM10 to promote efferocytosis of the apoptotic cells.
- Linnea Z. Drexhage
- , Shengpan Zhang
- & Quentin J. Sattentau
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Article
| Open AccessCell cycle arrest induces lipid droplet formation and confers ferroptosis resistance
How cell cycling coordinates with cell survival and death remains unclear. Here, the authors reveal a suppressive effect of cell cycle arrest on ferroptosis and propose a ferroptosis-inducing approach to treat slow-cycling, therapy-resistant cancers.
- Hyemin Lee
- , Amber Horbath
- & Boyi Gan
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Article
| Open AccessUnique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice
Invariant natural killer T (iNKT) cells have recently been reported to play a key role in adipose tissue homeostasis. Here, the authors show that adipose tissue iNKT cells mediate immune responses that control adipocyte turnover in mice.
- Sang Mun Han
- , Eun Seo Park
- & Jae Bum Kim
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Article
| Open AccessChemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
Deregulation of BCL-2 proteins ensures resistance to apoptosis. Here, the authors describe cytosolic BAX dimers, which in cancer cells inhibit BAX activation and they develop a strategy to modulate BAX dimers to potentiate BAX-mediated apoptosis.
- Nadege Gitego
- , Bogos Agianian
- & Evripidis Gavathiotis
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Article
| Open AccessMegakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels
Circulating cell-free DNA (cfDNA) has diagnostic potential, and clarifying its origins will aid in the minimally-invasive detection and monitoring of disease. Here, authors find that physiologically, megakaryocytes are major sources of cfDNA, while erythroblasts also release small amounts of cfDNA.
- Joshua Moss
- , Roni Ben-Ami
- & Yuval Dor
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Article
| Open AccessFarnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis
Ferroptosis is a regulated form of cell death occurring upon lipid peroxidation. Here, the authors discovered that activation of the Farnesoid X receptor by bile acids suppresses ferroptosis through upregulation of anti-ferroptotic genes.
- Juliane Tschuck
- , Lea Theilacker
- & Kamyar Hadian
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Article
| Open AccessPhosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization
How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.
- Yanxiang Meng
- , Sarah E. Garnish
- & James M. Murphy
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Article
| Open AccessLactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
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Article
| Open AccessFibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano
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Article
| Open AccessFGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice
Hepatic ischemia-reperfusion injury (IRI) is a common complication that occurs during hepatic resection and transplantation. Here the authors show that Hepatic stellate cells secrete FGF18 which alleviates hepatocyte injury by USP16/KEAP1/Nrf2 signaling.
- Gaozan Tong
- , Yiming Chen
- & XiaoKun Li
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Article
| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessStructural insights into FSP1 catalysis and ferroptosis inhibition
FSP1 suppress ferroptosis by reducing CoQ10, yet the underlying mechanism how FSP1 reduces CoQ remains unknown. Here, the authors reveal that the homodimerization of FSP1 via its unique CTD is required for the catalytic activity and ferroptosis suppression and provide insight potentially useful to drug design.
- Yun Lv
- , Chunhui Liang
- & Deyu Zhu
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Article
| Open AccessThe lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
Ferroptosis is an iron-dependent cell death mechanism that is emerging as a target for cancer therapy. Here, the authors find that lipoprotein-associated phospholipase A2 modulates ferroptosis resistance by controlling phospholipid metabolism.
- Mihee Oh
- , Seo Young Jang
- & Eun-Woo Lee
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Article
| Open AccessExtracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4
Dying cells display an “eat me” signal through phospholipid scrambling. Here, the authors show that activation of the plasma membrane-bound Xkr4 scramblase requires extracellular calcium as a “molecular glue” for connecting transmembrane regions.
- Panpan Zhang
- , Masahiro Maruoka
- & Jun Suzuki
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Article
| Open AccessA cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses
Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.
- Zhigui Zuo
- , Hao Yin
- & Qinyang Wang
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Article
| Open AccessNacα protects the larval fat body from cell death by maintaining cellular proteostasis in Drosophila
Protein homeostasis is crucial for maintaining cellular homeostasis. Here, the authors show that proteotoxic stress caused by Nacalpha mutants specifically and progressively induces cell death in the apoptosis-resistant Drosophila larval fat body.
- Takayuki Yamada
- , Yuto Yoshinari
- & Takashi Nishimura
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Review Article
| Open AccessChallenges in developing Geroscience trials
Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This article reports a discussion of a research Task Force on the challenges posed by the clinical research in Geroscience so that future gerotherapeutic clinical trials can be conducted successfully.
- Yves Rolland
- , Felipe Sierra
- & Alex Zhavoronkov
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Article
| Open AccessSNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development
The balance of stem cell maintenance, differentiation, and programmed death is critical for proper development. Here they show that SNIP1 is critical for stem cell survival and differentiation in the developing brain where it acts downstream of TGFb and NFkB and regulates PRC2 activities for governing cell fates.
- Yurika Matsui
- , Mohamed Nadhir Djekidel
- & Jamy C. Peng
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Article
| Open AccessIntermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
The application of dietary methionine intervention is of particular interest in the field of cancer therapy. Here the authors show that intermittent but not sustained deprivation of methionine promotes tumor ferroptosis and improves response to checkpoint inhibitors.
- Ying Xue
- , Fujia Lu
- & Weimin Wang
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Article
| Open AccessElevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation
Cancer cells with elevated 3’ end processing activities are vulnerable to CPAi because of transcriptomic disturbances caused by alternative polyadenylation and transcriptional readthrough as well as DNA damages when cells are proliferative.
- Yange Cui
- , Luyang Wang
- & Bin Tian
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Article
| Open AccessLysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34
iPLA2β produces lipid mediators and induces nuclear shrinkage in caspase-independent cell death. Here, the authors show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death mediated through GPR34 in pressure-overloaded mouse hearts, leading to cardiac dysfunction.
- Ryuta Sugihara
- , Manabu Taneike
- & Kinya Otsu
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Article
| Open Accessp53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism
p53 inactivation is nearly universal in small-cell lung cancer (SCLC), but its tumor suppressive role in this cancer type is poorly understood. Here the authors show that intertumoral heterogeneity in SCLC influences the biological mechanisms of p53-mediated tumor suppression and identify a role for cyclophilins in p53-dependent necrotic cell death.
- Jonuelle Acosta
- , Qinglan Li
- & David M. Feldser
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Article
| Open AccessStructures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity
The human tumor suppressor p53 interacts with the BCL-2 family proteins to regulate apoptosis. Here, the authors solve the structures of p53 in complex with the antiapoptotic protein BCL-2 and suggest a mechanism by which p53 promotes apoptosis by competitively antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family proteins.
- Hudie Wei
- , Haolan Wang
- & Yongheng Chen
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Article
| Open AccessCytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle
The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.
- Paul T. Morse
- , Gonzalo Pérez-Mejías
- & Maik Hüttemann
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Article
| Open AccessOn the mechanisms of lysis triggered by perturbations of bacterial cell wall biosynthesis
Inhibition of bacterial cell wall synthesis by β-lactam antibiotics results in a loss of cell wall integrity, but cells die via a combination of downstream events involving metabolic perturbations and oxidative damage. Here, Kawai et al. identify key enzymatic steps that stimulate the generation of reactive oxygen species and highlight the role of iron homeostasis in the lethal effects mediated by oxidative damage.
- Yoshikazu Kawai
- , Maki Kawai
- & Jeff Errington
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Article
| Open AccessSLC7A11 expression level dictates differential responses to oxidative stress in cancer cells
The cystine transporter SLC7A11 protects cancer cells from oxidative stress by supporting glutathione synthesis. Here, the authors show that the expression level of SLC7A11 leads to different outcomes depending on context, so high expression promotes primary tumour growth but promotes disulfide stress under oxidative stress conditions and impairs metastasis.
- Yuelong Yan
- , Hongqi Teng
- & Boyi Gan
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Article
| Open AccessTisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice
Cardiac I/R injury is a deleterious issue in the clinic. Here, the authors show that Tisp40 facilitates HBP flux and protein O-GlcNAcylation through binding to the promoter of GFPT1, thereby preventing cardiac I/R injury.
- Xin Zhang
- , Can Hu
- & Qi-Zhu Tang
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Article
| Open AccessSMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance
The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.
- Bujamin H. Vokshi
- , Guillaume Davidson
- & Gabriel G. Malouf
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Article
| Open AccessDynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.
- Danielle S. Potter
- , Ruochen Du
- & Anthony Letai
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Article
| Open AccessRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis
The mechanism underlying regorafenib’s hepatotoxicity during anticancer therapy remains elusive. Here, the authors show regorafenib inhibits the phosphorylation of EphA2 at Ser897 resulting in the accumulation of p53 and contributes to hepatocytes apoptosis and the formation of hepatotoxicity.
- Hao Yan
- , Wentong Wu
- & Peihua Luo
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Article
| Open AccessUDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis
The mechanism underlying hepatocytes apoptosis, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here, the authors identify UGDH and its catalytic product UDP-glucuronate as suppressors of NASH-associated liver damage by inhibiting RIPK1- dependent hepatocyte apoptosis.
- Tao Zhang
- , Na Zhang
- & Jinyang Gu
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Article
| Open AccessTargeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy
The clinical success of restoring P53 for cancer therapy has been limited due to toxicity. Here, the authors identify USP2 as an upstream regulator of VPRBP-mediated degradation of p53 and PD-L1 and demonstrate the efficacy of combining USP2 inhibitor and PD-L1/PD-1 immune checkpoint blockade in cancers.
- Jingjie Yi
- , Omid Tavana
- & Wei Gu
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Article
| Open AccessPRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer
Despite being an effective treatment for hepatocellular carcinoma (HCC), resistance to oxaliplatin presents a major obstacle. Here, the authors identify PRMT3-induced methylation of IGF2BP1 resulting in HEG1 stabilisation as a mechanism of oxaliplatin resistance in HCC.
- Yunxing Shi
- , Yi Niu
- & Binkui Li
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Article
| Open AccessA mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination
Ferroptosis is an iron-dependent form of cell death whose role in infectious diseases is being elucidated. Here, Qiang et al. show that PtpA, an effector secreted by Mycobacterium tuberculosis, induces ferroptosis by hijacking host arginine methyltransferase PRMT6 to promote its pathogenicity and dissemination.
- Lihua Qiang
- , Yong Zhang
- & Jing Wang
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Article
| Open AccessExecutioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis
During apoptosis, mitochondrial outer membrane permeabilization results in cytosolic mitochondrial RNA (mtRNA). Here, the authors demonstrate that caspase-3/7 inhibition promotes a cytosolic mtRNA-driven Type I interferon response via MDA5/MAVS/IRF3, increasing the immunogenicity of chemotherapy-induced apoptosis.
- Shane T. Killarney
- , Rachel Washart
- & Kris C. Wood
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Article
| Open AccessTHADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass
THADA has been identified as a type 2 diabetes-associated gene whose function is not fully understood. Here the authors report that THADA deficiency protects mice from hyperglycemia and glucose intolerance by promoting insulin secretion and inhibiting β-cell apoptosis, suggesting THADA could be explored as a potential therapeutic target for diabetes.
- Yuqing Zhang
- , Shan Han
- & Han Zhao
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Article
| Open AccessThe transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice
Aggravation of liver steatosis shifts the hepatocellular death mode from apoptosis to necroptosis in acute and chronic liver damage. Here the authors report that the transcription factor ATF3 regulates this shift through the induction of RIPK3, a regulator of necroptosis.
- Yuka Inaba
- , Emi Hashiuchi
- & Hiroshi Inoue
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Article
| Open AccessExpansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis
The induction of immunogenic cell death (ICD) can potentiate antitumour immunity. Here the authors show that USP18, a negative regulator of IFN signaling protects cancer cells from ICD by suppressing the expression of canonical and non-canonical IFN-stimulated genes.
- Kei-ichiro Arimoto
- , Sayuri Miyauchi
- & Dong-Er Zhang
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Article
| Open AccessAn entosis-like process induces mitotic disruption in Pals1 microcephaly pathogenesis
Entosis is a process of cell cannibalism observed in cancer. Here, Sterling and colleagues report that entosis can also play a role in brain development and can contribute to the pathogenesis of microcephaly.
- Noelle A. Sterling
- , Jun Young Park
- & Seonhee Kim
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Article
| Open AccessInsights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8
The multifunctional GSDMB protein is an important molecule in human immunity. Here, the authors decipher the molecular mechanisms of GSDMB targeting by the bacterial virulence factor IpaH7.8 and provide insights into GSDMB-mediated pyroptosis.
- Hang Yin
- , Jian Zheng
- & Heng Zhang
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Article
| Open AccessUnique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis.
- Hirofumi Nagao
- , Ashok Kumar Jayavelu
- & C. Ronald Kahn