Cell Death & Disease最新文献

{"title":"Absent in melanoma 2: a potent suppressor of retinal pigment epithelial-mesenchymal transition and experimental proliferative vitreoretinopathy.","authors":"Yu Chen, Mingyuan Jiang, Liping Li, Shanshan Yang, Zuimeng Liu, Shiwen Lin, Wanxiao Wang, Jinyang Li, Feng Chen, Qiang Hou, Xiaoyin Ma, Ling Hou","doi":"10.1038/s41419-025-07367-9","DOIUrl":"10.1038/s41419-025-07367-9","url":null,"abstract":"<p><p>Epithelial-to-mesenchymal transition (EMT) is a critical and complex process involved in normal embryonic development, tissue regeneration, and tumor progression. It also contributes to retinal diseases, such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Although absent in melanoma 2 (AIM2) has been linked to inflammatory disorders, autoimmune diseases, and cancers, its role in the EMT of the retinal pigment epithelium (RPE-EMT) and retinal diseases remains unclear. The present study demonstrated that AIM2 functions as a potent suppressor of RPE cell proliferation and EMT to maintain retinal homeostasis. Transcriptome analysis using RNA-sequencing (RNA-Seq) revealed that AIM2 was significantly downregulated in primary human RPE (phRPE) cells undergoing EMT and proliferation. Consequently, Aim2-deficient mice showed morphological changes and increased FN expression in RPE cells under physiological conditions, whereas AIM2 overexpression in phRPE cells inhibited EMT. In a retinal detachment-induced PVR mouse model, AIM2 deficiency promotes RPE-EMT, resulting in severe experimental PVR. Clinical samples further confirmed the downregulation of AIM2 in the PVR membranes from patients. Kyoto Encyclopedia of Genes and Genome analysis revealed that the PI3K-AKT signaling pathway was significantly related to RPE-EMT and that AIM2 inhibited AKT activation in RPE cells by reducing its phosphorylation. Moreover, treatment with eye drops containing an AKT inhibitor alleviated RPE-EMT and the severity of experimental PVR. These findings provide new insights into the complex mechanisms underlying RPE-EMT and PVR pathogenesis, with implications for rational strategies for potential therapeutic applications in PVR by targeting RPE-EMT.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"49"},"PeriodicalIF":8.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZBP1-mediated PANoptosis is a crucial lethal form in diverse keratinocyte death modalities in UVB-induced skin injury.","authors":"Xuechan Bi, Min Li, Yiming Guo, Mengyao Hu, Yujie Chen, Ni Lian, Sihan Chen, Min Li, Heng Gu, Xu Chen","doi":"10.1038/s41419-025-07351-3","DOIUrl":"10.1038/s41419-025-07351-3","url":null,"abstract":"<p><p>UVB irradiation induces diverse modalities of regulatory cell death in keratinocytes. Recently, the pattern of coexistence of pyroptosis, apoptosis, and necroptosis has been termed PANoptosis; however, whether PANoptosis occurs in keratinocytes in UVB-induced skin injury remains unclear. We observed that the key molecules of GSDMD-mediated pyroptosis, apoptosis, and necroptosis, which are N-terminal GSDMD, cleaved caspase-3/PARP, and phosphorylated MLKL, respectively, were elevated in keratinocytes of UVB-challenged mice and human skin tissue. Through keratinocyte-specific gene knockout or using corresponding inhibitors, we found that individual inhibition of GSDMD-mediated pyroptosis, caspase-3-mediated apoptosis, or MLKL-mediated necroptosis did not reduce the overall level of keratinocyte death after UVB exposure, and that the other two pathways maintained the activation. However, when the PANoptosome sensor ZBP1 was knocked out, keratinocyte death was reduced and epidermal thickening was alleviated in UVB-challenged mice. In conclusion, our study demonstrated that UVB irradiation induces ZBP1-mediated PANoptosis in keratinocytes, which is a crucial lethal form in diverse keratinocyte death modalities in UVB-induced skin injury. The above findings provide a new insight on the complexity of regulated cell death modalities in keratinocytes exposed to UV irradiation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"44"},"PeriodicalIF":8.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment.","authors":"Jiarui Lv, Yanan Wang, Jiacheng Lv, Cuiting Zheng, Xinyu Zhang, Linyan Wan, Jiayang Zhang, Fangming Liu, Hongbing Zhang","doi":"10.1038/s41419-025-07332-6","DOIUrl":"10.1038/s41419-025-07332-6","url":null,"abstract":"<p><p>TSC2, a suppressor of mTOR, is inactivated in up to 20% of HBV-associated liver cancer. This subtype of liver cancer is associated with aggressive behavior and early recurrence after hepatectomy. Being the first targeted regimen for advanced liver cancer, sorafenib has limited efficacy in HBV-positive patients. In this study, we observed that mTOR-activated cells, due to the loss of either TSC2 or PTEN, were insensitive to the treatment of sorafenib. Mechanistically, HSP70 enhanced the interaction between active mTOR-potentiated CREB1 and CREBBP to boost the transcription of the antioxidant response regulator SESN3. In return, elevated SESN3 enhanced cellular antioxidant capacity and rendered cells resistant to sorafenib. Pifithrin-μ, an HSP70 inhibitor, synergized with sorafenib in the induction of ferroptosis in mTOR-activated liver cancer cells and suppression of TSC2-deficient hepatocarcinogenesis. Our findings highlight the pivotal role of the mTOR-CREB1-SESN3 axis in sorafenib resistance of liver cancer and pave the way for combining pifithrin-μ and sorafenib for the treatment of mTOR-activated liver cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"42"},"PeriodicalIF":8.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway.","authors":"Teng Sun, Jialei Li, Shuang Wang, Yu Han, Xiangyu Tao, Min Yuan, Zhijie Jing, Ting Liu, Yuehong Qi, Siqi Liu, Yanlin Feng, Jiasong Chang, Lan Zhou, Lijuan Gao, Jianyun Shi, Ruihong Ning, Jimin Cao","doi":"10.1038/s41419-025-07360-2","DOIUrl":"10.1038/s41419-025-07360-2","url":null,"abstract":"<p><p>Programmed necrosis/necroptosis greatly contributes to the pathogenesis of cardiac disorders including myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondria-dependent death pathway, is poorly understood. Synaptotagmin-1 (Syt1), a Ca²⁺ sensor, is originally identified in nervous system and mediates synchronous neurotransmitter release. The later findings of Syt1 expressions in many non-neuronal tissues including muscles suggest that Syt1 may exert important functions beyond regulation of neurotransmitter release. Syt1 is highly expressed in cardiomyocytes and has been used as an extracellular molecular probe for SPECT imaging of cardiac cell death in acute myocardial infarction. However, whether Syt1 functions in the pathogenesis of cardiac disorders and what is the molecular etiology have not yet been clarified. We showed here that Syt1 expression was significantly down-regulated in mice I/R injured heart tissues, H₂O₂-challenged cardiomyocytes and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Enforced expression of Syt1 significantly inhibited myocardial necrotic cell death and interstitial fibrosis, and improved cardiac function in mice subjected to I/R operation. In exploring the underlying mechanisms, we found that Syt1 interacted with Parkin and promoted Parkin-catalyzed CypD ubiquitination, thus inhibited mitochondrial membrane permeability transition pore (mPTP) opening and ultimately suppressed cardiomyocyte necrosis. We further found that Syt1 expression was negatively regulated by miR-193b-3p. MiR-193b-3p regulated cardiomyocyte necrosis and mPTP opening by targeting Syt1. Our present work revealed a novel regulatory model of myocardial necrosis composed of miR-193b-3p, Syt1, Parkin, and CypD, which may provide potential therapeutic targets and strategies for heart protection.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"45"},"PeriodicalIF":8.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway.","authors":"Pei Huang, Guangli Yang, Pingping Zhang, Yin Zhu, Yaning Guan, Jian Sun, Qian Li, Yang An, Xiaoqi Shi, Juanjuan Zhao, Chaohong Liu, Zhixu He, Yan Chen, Zuochen Du","doi":"10.1038/s41419-025-07352-2","DOIUrl":"10.1038/s41419-025-07352-2","url":null,"abstract":"<p><p>The involvement of B lymphocytes in the pathogenesis of rheumatoid arthritis (RA) is well-established, with their early and aberrant activation being a crucial factor. However, the mechanisms underlying this abnormal activation in RA remain incompletely understood. In this study, we identified a significant reduction in MAPK4 expression in both RA patients and collagen-induced arthritis (CIA) mouse models, which correlates with disrupted B cell activation. Using MAPK4 knockout (KO) mice, we demonstrated that MAPK4 intrinsically promotes the differentiation of marginal zone (MZ) B cells. Loss of MAPK4 in KO mice enhances proximal BCR signaling and activates the PI3K-AKT-mTOR pathway, leading to heightened B cell proliferation. Notably, B cells from MAPK4 KO mice produce significantly higher levels of IL-6, a key pro-inflammatory cytokine in RA. Furthermore, MAPK4 KO mice exhibit impaired T cell-independent humoral immune responses. Mechanistically, MAPK4 inhibits the activation of the PI3K signaling pathway in B cells by activating the IRF4-SHIP1 pathway. Treatment with the MAPK4 agonist Vacquinol-1 enhances MZ B cell differentiation in WT mice and reduces IL-6 secretion in CIA mouse models. In summary, this study reveals the diverse roles of MAPK4 in regulating of B cell functions, with potential implications for developing therapeutic strategies for RA and related autoimmune diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"43"},"PeriodicalIF":8.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment.","authors":"Darya Yanushko, Beatriz German Falcon, Rana El Bizri, Despoina Pervizou, Robin Dolgos, Céline Keime, Tao Ye, Christelle Thibault-Carpentier, Clementine Le Magnen, Sandrine Henri, Gilles Laverny, Daniel Metzger","doi":"10.1038/s41419-025-07361-1","DOIUrl":"10.1038/s41419-025-07361-1","url":null,"abstract":"<p><p>Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor genes PTEN and TP53 are frequently mutated in prostate cancer and are predictive of early metastatic dissemination and unfavorable patient outcomes. The progression of solid tumors to metastasis is often associated with increased cell plasticity, but the complex events underlying TP53-loss-induced disease aggressiveness remain incompletely understood. Using genetically engineered mice, we show that Trp53 deficiency in Pten-null prostatic epithelial cells (PECs) does not impact early cell proliferation and neoplasia formation, nor growth arrest and senescence entry at a later time. However, Trp53-deficiency enhances invasive adenocarcinoma development and promotes metastatic cell dissemination. Importantly, our single-cell transcriptomic and chromatin accessibility analyses combined with histological examinations uncovered an epithelial cell population characterized by an induction of Jak/Stat3 signaling and displaying mesenchymal features. Moreover, we show that the transcriptomic signature of this cell population is prominent in tumors of patients with high-risk prostate cancer or metastatic disease. In addition, our in vivo and organoid-based experiments provide evidence that PEC plasticity occurs through bi-directional communication with cancer-associated fibroblasts (CAFs). Thus, our study demonstrates that p53 loss induces a protumorigenic crosstalk between PECs and CAFs, and identifies new vulnerabilities that might be targeted to limit cancer progression.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"46"},"PeriodicalIF":8.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair.","authors":"Yuchen Wei, Peng Wang, Jianhui Zhao, Xin Fan, Jun Jiang, Xiuli Mu, Yuzhou Wang, Angang Yang, Rui Zhang, Shijie Hu, Zhangyan Guo","doi":"10.1038/s41419-025-07363-z","DOIUrl":"10.1038/s41419-025-07363-z","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common malignant primary brain cancer with poor prognosis due to the resistant to current treatments, including the first-line drug temozolomide (TMZ). Accordingly, it is urgent to clarify the mechanism of chemotherapeutic resistance to improve the survival rate of patients. In the present study, by integrating comprehensive non-coding RNA-seq data from multiple cohorts of GBM patients, we identified that a series of miRNAs are frequently downregulated in GBM patients compared with the control samples. Among them, a high level of miR-124 is closely associated with a favorable survival rate in the clinical patients. In the phenotype experiment, we demonstrated that miR-124 overexpression increases responsiveness of GBM cells to TMZ-induced cell death, and vice versa. In the mechanistic study, we for the first time identified that RAD51, a key functional molecule in DNA damage repair, is a novel and bona fide target of miR-124 in GBM cells. Given that other miR-124-regulated mechanisms on TMZ sensitivity have been reported, we performed recue experiment to demonstrate that RAD51 is essential for miR-124-mediated sensitivity to TMZ in GBM cells. More importantly, our in vivo functional experiment showed that combinational utilization of miR-124 overexpression and TMZ presents a synergetic therapeutic benefit in the orthotopic GBM mice model. Taken together, we rationally explained a novel and important mechanism of the miR-124-mediated high sensitivity to TMZ-induced cell death in GBM and provided evidence to support that miR-124-RAD51 regulatory axis could be a promising candidate in the comprehensive treatment with TMZ in GBM.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"47"},"PeriodicalIF":8.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.","authors":"Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt","doi":"10.1038/s41419-024-07312-2","DOIUrl":"10.1038/s41419-024-07312-2","url":null,"abstract":"<p><p>Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"40"},"PeriodicalIF":8.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses.","authors":"Wenke Wang, Boquan Wu, Mingjun Hao, Sichong Chen, Ruiting Cong, Wenjie Wu, Pengbo Wang, Qiaoyi Zhang, Pengyu Jia, Yuequn Song, Bo Liu, Siyao Qu, Jian-Fei Pei, Da Li, Naijin Zhang","doi":"10.1038/s41419-025-07362-0","DOIUrl":"10.1038/s41419-025-07362-0","url":null,"abstract":"<p><p>Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic rewiring to enhance macrophage effector functions remain unclear. Here, we demonstrated that the metabolic reprogramming in inflammatory macrophages depended on the acetylation of CLYBL, a citramalyl-CoA lyase, at lysine 154 (K154), and blocking CLYBL-K154 acetylation restricted the release of pro-inflammatory factors. Mechanistically, we found a crucial AMPK-CLYBL acetylation positive feedback loop, triggered by toll-like receptors (TLRs), involving AMPK hypophosphorylation and CLYBL hyperacetylation. The deacetylase enzyme SIRT2 acted as the bridge between AMPK phosphorylation and CLYBL acetylation, thereby regulating macrophage polarization and the release of pro-inflammatory cytokines. Furthermore, CLYBL hypoacetylation decreased monocyte infiltration, thereby alleviating cardiac remodeling. These findings suggest that the AMPK-CLYBL acetylation positive feedback loop serves as a metabolic switch driving inflammatory response and inhibiting CLYBL-K154 acetylation may offer a promising therapeutic strategy for inflammatory response-related disorders.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"41"},"PeriodicalIF":8.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNAi-based ALOX15B silencing augments keratinocyte inflammation in vitro via EGFR/STAT1/JAK1 signalling.","authors":"Megan A Palmer, Rebecca Kirchhoff, Claudia Buerger, Yvonne Benatzy, Nils Helge Schebb, Bernhard Brüne","doi":"10.1038/s41419-025-07357-x","DOIUrl":"10.1038/s41419-025-07357-x","url":null,"abstract":"<p><p>Arachidonate 15-lipoxygenase type B (ALOX15B) peroxidises polyunsaturated fatty acids to their corresponding fatty acid hydroperoxides, which are subsequently reduced into hydroxy-fatty acids. A dysregulated abundance of these biological lipid mediators has been reported in the skin and blood of psoriatic compared to healthy individuals. RNAscope and immunohistochemistry revealed increased ALOX15B expression in lesional psoriasis samples. Using a cytokine cocktail containing IL-17A, interferon-gamma and tumour necrosis factor-alpha to produce a psoriasis-like phenotype, a role for ALOX15B in human epidermal keratinocyte inflammation was investigated. siRNA-mediated silencing of ALOX15B increased CCL2 expression and secretion. In addition to CCL2, secretion of CCL5 and CXCL10 were elevated in skin equivalents treated with lipoxygenase inhibitor ML351. Inhibition of the JAK1/STAT1 pathway reversed the enhanced CCL2 expression found with ALOX15B silencing. Previous studies have linked epidermal growth factor receptor (EGFR) inhibition with the upregulation of cytokines including CCL2, CCL5 and CXCL10. ALOX15B silencing reduced EGFR expression and inhibition of EGFR signalling potentiated the effect of ALOX15B silencing on increased CCL2, CCL5 and CXCL10 expression. Confirming previous findings, gene expression of cholesterol biosynthesis genes was reduced via reduced ERK phosphorylation. Reduced ERK phosphorylation was dependant on EGFR and NRF2 activation. Furthermore, plasma membrane lipids were investigated via confocal microscopy, revealing reduced cholesterol and lipid rafts. This study suggests a role for ALOX15B in keratinocyte inflammation through modulation of lipid peroxidation and the EGFR/JAK1/STAT1 signalling axis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"39"},"PeriodicalIF":8.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}