Cell Death Discovery最新文献

{"title":"Thy1-YFP: an effective tool for single cell tracing from neuronal progenitors to mature functionally active neurons.","authors":"Ante Plećaš, Katarina Kapuralin, Leonarda Grandverger, Dinko Mitrečić, Ivan Alić","doi":"10.1038/s41420-025-02297-z","DOIUrl":"10.1038/s41420-025-02297-z","url":null,"abstract":"<p><p>The differentiation of mouse neurons is a complex process involving cell maturation and branching, occurring during both, embryonic development and differentiation in vitro. To study mouse neuronal morphology, we used the Thy1 YFP-16 mouse strain. Although this mouse strain was described over twenty years ago, detailed studies on projections outgrowth and morphology of neurons are still lacking. The main goal of our study was to analyse the differentiation patterns of neural stem cells, including markers of differentiation, colocalization patterns, synaptic markers and the tracing of cell projections during differentiation in vitro. The neural stem cells were isolated from embryos at embryonic day 14.5 as well as newborn pups and differentiated into neurons and astrocytes. Our data showed a significant decrease of neural stem cells markers and a substantial increase in neuronal markers during differentiation, analysed by immunocytochemistry, quantitative PCR and western blot. To assess synaptic maturation, neurons were further analysed by quantitative PCR and immunocytochemistry. Expression of synaptic markers were increased during differentiation in vitro. At the 7^th day in vitro differentiation, expression of synaptic markers in both YFP positive and YFP negative neurons were at comparable levels. Finally, our data revealed a significant increase in all measured morphological parameters: Filament Area, Filament Length, Filament No. Terminal Points and Sholl Intersections in YFP positive/MAP2 positive neurons compared to YFP negative/MAP2 positive neurons. These findings suggest that YFP is an effective tool for cell tracing both in vivo and in vitro, making it valuable for morphological studies during development as well as in the context of neurodegenerative disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"18"},"PeriodicalIF":6.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exocyst complex component 1 (Exoc1) loss in dormant oocyte disrupts c-KIT and growth differentiation factor (GDF9) subcellular localization and causes female infertility in mice.","authors":"Chi Lieu Kim Nguyen, Yumeno Kuba, Hoai Thu Le, Hossam Hassan Shawki, Natsuki Mikami, Madoka Aoki, Nanako Yasuhara, Hayate Suzuki, Saori Mizuno-Iijima, Shinya Ayabe, Yuki Osawa, Tomoyuki Fujiyama, Tra Thi Huong Dinh, Miyuki Ishida, Yoko Daitoku, Yoko Tanimoto, Kazuya Murata, Woojin Kang, Masatsugu Ema, Yuji Hirao, Atsuo Ogura, Satoru Takahashi, Fumihiro Sugiyama, Seiya Mizuno","doi":"10.1038/s41420-025-02291-5","DOIUrl":"10.1038/s41420-025-02291-5","url":null,"abstract":"<p><p>A limited number of female germ cells support reproduction in many mammals. The follicle, composed of oocytes and supporting granulosa cells, forms the basis of oogenesis. Crosstalk between oocytes and granulosa cells is essential for the formation, dormancy, re-awakening, and maturation of oocytes. The oocyte expresses c-KIT and growth differentiation factor-9 (GDF-9), which are major factors in this crosstalk. The downstream signalling pathways of c-KIT and GDF-9 have been well-documented; however, their intra-oocyte trafficking pathway remains unclear. Our study reveals that the exocyst complex, a heterotetrameric protein complex important for tethering in vesicular transport, is important for proper intra-oocyte trafficking of c-KIT and GDF9 in mice. We found that depletion of oocyte-specific EXOC1, a component of the exocyst complex, impaired oocyte re-awakening and cyst breakdown, and inhibited granulosa cell proliferation during follicle growth. The c-KIT receptor is localised on the oocyte plasma membrane. The oocyte-specific Kit conditional knockout mice were reported to exhibit impaired oocyte re-awakening and reduced oocyte cyst breakdown. GDF9 is a protein secreted extracellularly in the oocyte. Previous studies have shown that Gdf9 knockout mice impaired proliferation and granulosa cell multilayering in growing follicles. We found that both c-KIT and GDF9 abnormally stuck in the EXOC1-depleted oocyte cytoplasm. These abnormal phenotypes were also observed in oocytes depleted of exocyst complex members EXOC3 and EXOC7. These results clearly show that the exocyst complex is essential for proper intra-oocyte trafficking of c-KIT and GDF9. Inhibition of this complex causes complete loss of female fertility in mice. Our findings build a platform for research related to trafficking mechanisms of vital crosstalk factors for oogenesis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"17"},"PeriodicalIF":6.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions.","authors":"Martin Škandík, Lara Friess, Guillermo Vázquez-Cabrera, Lily Keane, Kathleen Grabert, Mireia Cruz De Los Santos, Mercedes Posada-Pérez, Austeja Baleviciute, Mathilde Cheray, Bertrand Joseph","doi":"10.1038/s41420-025-02295-1","DOIUrl":"https://doi.org/10.1038/s41420-025-02295-1","url":null,"abstract":"<p><p>The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted from additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to the stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes-CAPG, LGALS3BP, NRIP1, and P2RY12-were found to share regulatory patterns in response to both aging and extrinsic activation. An in-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human-aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"16"},"PeriodicalIF":6.1,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRAT downregulation promotes ovarian cancer progression by facilitating mitochondrial metabolism through decreasing the acetylation of PGC-1α.","authors":"Zhen Zhang, Shuhua Zhao, Xiaohui Lv, Yan Gao, Qian Guo, Yanjie Ren, Yuanyuan He, Yihua Jin, Hong Yang, Shujuan Liu, Xiaohong Zhang","doi":"10.1038/s41420-025-02294-2","DOIUrl":"https://doi.org/10.1038/s41420-025-02294-2","url":null,"abstract":"<p><p>Mitochondrial dysfunctions are closely associated with different types of disease, including cancer. Carnitine acetyltransferase (CRAT) is a mitochondrial-localized enzyme catalyzing the reversible transfer of acyl groups from an acyl-CoA thioester to carnitine and regulates the ratio of acyl-CoA/CoA. Our bioinformatics analysis using public database revealed a significant decrease of CRAT expression in ovarian cancer (OC). However, the functions of CRAT have rarely been investigated in human cancers, especially in OC. Here, we found a frequent down-regulation of CRAT in OC, which is mainly caused by up-regulation of miR-132-5p. Downregulation of CRAT was significantly associated with shorter survival time for patients with OC. Forced expression of CRAT suppressed OC growth and metastasis by inducing cell cycle arrest and epithelial to mesenchymal transition (EMT). By contrast, CRAT knockdown promoted OC growth and metastasis. Mechanistically, we found that CRAT downregulation promoted OC growth and metastasis by increasing mitochondrial biogenesis to facilitate mitochondrial metabolism through reducing the acetylation of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α). In summary, CRAT functions as a critical tumor suppressor in OC progression by enhancing PGC-1α-mediated mitochondrial biogenesis and metabolism, suggesting CRAT as a potential therapeutic target in treatment of OC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"15"},"PeriodicalIF":6.1,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the mechanisms of long non-coding RNAs in ferroptosis: insights into its clinical significance in cancer progression and immunology.","authors":"Shengming Ou, Xiaoya Nie, Xiangyu Qiu, Xin Jin, Geyan Wu, Rongxin Zhang, Jinrong Zhu","doi":"10.1038/s41420-025-02290-6","DOIUrl":"https://doi.org/10.1038/s41420-025-02290-6","url":null,"abstract":"<p><p>A new type of nonapoptotic, iron-dependent cell death induced by lipid peroxidation is known as ferroptosis. Numerous pathological processes, including inflammation and cancer, have been demonstrated to be influenced by changes in the ferroptosis-regulating network. Long non-coding RNAs (LncRNAs) are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that lncRNAs can interfere with the progression of ferroptosis by modulating ferroptosis-related genes directly or indirectly. Despite evidence implicating lncRNAs in cancer and inflammation, studies on their mechanisms and therapeutic potential remain scarce. We investigate the mechanisms of lncRNA-mediated regulation of inflammation and cancer immunity, assessing the feasibility and challenges of lncRNAs as therapeutic targets in these conditions.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"14"},"PeriodicalIF":6.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helicobacter pylori reduces METTL14-mediated VAMP3 m⁶A modification and promotes the development of gastric cancer by regulating LC3C-mediated c-Met recycling.","authors":"Xixi Cui, Mingjie Chang, Yuqiong Wang, Jiayi Liu, Zenghui Sun, Qiyu Sun, Yundong Sun, Juchao Ren, Wenjuan Li","doi":"10.1038/s41420-025-02289-z","DOIUrl":"https://doi.org/10.1038/s41420-025-02289-z","url":null,"abstract":"<p><p>Helicobacter pylori (H. pylori) plays an important role in the malignant transformation of the gastric mucosa from chronic inflammation to cancer. However, the mechanisms underlying the epigenetic regulation of gastric carcinogenesis mediated by H. pylori remain unclear. Here, we uncover that H. pylori inhibits METTL14 by upregulating ATF3. METTL14 inhibits gastric cancer (GC) cell proliferation and metastasis in vitro and in vivo. Downregulation of METTL14 inhibits Vesicle-associated membrane protein-3 (VAMP3) by reducing the m⁶A modification level of VAMP3 mRNA and the stability of IGF2BP2-dependent mRNA. H. pylori also accelerates the malignant progression of GC by regulating VAMP3/LC3C-mediated c-Met recycling. Moreover, the expression of METTL14 and VAMP3 in Hp+ chronic gastritis tissues is much lower than that in Hp- chronic gastritis tissues. METTL14 and VAMP3 expression levels are downregulated notably in cancerous tissues of patients with GC. Therefore, our results show a novel METTL14-VAMP3-LC3C-c-Met signalling axis in the GC development mediated by H. pylori infection, which reveals a novel m⁶A epigenetic modification mechanism for GC and provides potential prognostic biomarkers for GC progression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"13"},"PeriodicalIF":6.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK14 regulates the development and repair of lung.","authors":"Jian-Wei Chen, Yu-Xiang Wang, Rong-Rong Gao, Lan-Yue Ma, Jing Zhong, Jia-Xin Yang, Zhao-Hua Deng, Yu-Yan Li, Xiao-Ling Li, Ya-Hai Shu, Wen-Jing Guo, Zi-Yuan Zhou, Xiao Yu Tian, Jinjin Ma, Yang Liu, Qi Chen","doi":"10.1038/s41420-025-02292-4","DOIUrl":"https://doi.org/10.1038/s41420-025-02292-4","url":null,"abstract":"<p><p>Cyclin-dependent kinases (CDK) 14 regulates cell cycle, tumor expansion by influencing the downstream targets of the canonical Wnt signaling pathway. However, the function of CDK14 during organ development and regeneration has not been investigated in genetically-modified animals. Here, we found that genetic ablation of Cdk14 influenced pulmonary vascular endothelial cells and alveolar epithelial cells during mice embryonic development as well as repair of lung after bleomycin or lipopolysaccharide induced injury. Genetic knockout of Cdk14 and the CDK14 covalent inhibitor FMF-04-159-2 resulted in reduction of pulmonary vessel covered area and epithelial cell number, exhibiting increased mortality and more severe lung damage after injury. Mechanistically, Cdk14 ablation inhibited the proliferation of epithelial and vascular endothelial cells, inducing cell cycle arrest at the G₂/M phase. Through RNA-seq analysis of both endothelial and epithelial cells, we found that knockdown of Cdk14 controls the expression of signal transducers and activator of transcription 1 (STAT1) as well as associated genes in interferon signaling. Disruption of Cdk14 interferes with IFN-γ induced lung repair in vivo, suggesting potential crosstalk of CDK14 signaling and IFN-γ pathway. Our work highlights the importance of Cdk14 in lung development and regenerative repair through an uncharacterized CDK14- IFN-γ signaling axis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"12"},"PeriodicalIF":6.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pir-hsa-216911 inhibit pyroptosis in hepatocellular carcinoma by suppressing TLR4 initiated GSDMD activation.","authors":"Zhouxiang Liao, Lichao Yang, Xiaojing Cheng, Xuejing Huang, Qi Zhang, Daoqiang Wen, Zhenyu Song, Yasi Li, Sha Wen, Yongfeng Li, Meizhen Ou, Zhangnan Huang, Tianqi Liu, Min He","doi":"10.1038/s41420-024-02285-9","DOIUrl":"https://doi.org/10.1038/s41420-024-02285-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a global health concern, ranking as the fourth leading cause of cancer-related deaths worldwide. However, the role of piwi-interacting RNAs (piRNAs) in HCC processes has not been extensively explored. Through small RNA sequencing, our study identified a specific piRNA, pir-hsa-216911, which is highly expressed in HCC cells. This overexpression of pir-hsa-216911 promotes HCC cell invasion and inhibits cell death, particularly pyroptosis. Knocking out pir-hsa-216911 led to increased cell pyroptosis activity, resulting in the activation of caspase-1 and GSDMD. Further analysis revealed that pir-hsa-216911 targets and suppresses TLR4, a key gene associated with pyroptosis in HCC. In the Huh7 cell line, pir-hsa-216911 knockout confirmed its role in suppressing the TLR4/NFκB/NLRP3 pathway by silencing TLR4. Knocking out pir-hsa-216911 significantly inhibited the formation of Huh7 xenograft tumor. In HCC patients, pir-hsa-216911 was highly expressed in HCC tumor samples with steatosis, suppressing TLR4 expression and inhibiting GSDMD activation. This study introduces pir-hsa-216911 as a new high-expressing piRNA in HCC, which inhibits pyroptosis by silencing TLR4 to suppress GSDMD activation. These findings have significant implications for HCC molecular subtyping and as a potential target for cancer therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"11"},"PeriodicalIF":6.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GILT stabilizes cofilin to promote the metastasis of prostate cancer.","authors":"Dunsheng Han, Zhiming Wu, Cong Zhang, Ziwei Wei, Fan Chao, Xuefeng Xie, Jinke Liu, Yufeng Song, Xiaoming Song, Dingchang Shao, Shiyu Wang, Guoxiong Xu, Gang Chen","doi":"10.1038/s41420-025-02288-0","DOIUrl":"https://doi.org/10.1038/s41420-025-02288-0","url":null,"abstract":"<p><p>Gamma-interferon-induced lysosomal thiol reductase (GILT), known for catalyzing disulfide bond reduction, is involved in various physiological processes. While the involvement of GILT in the development of various tumors has been demonstrated, the mechanisms underlying its regulation in prostate cancer (PCa) are not fully understood. In the present study, we confirmed that GILT was significantly upregulated in PCa and facilitated tumor metastasis. Mechanistically, GILT stabilized the cofilin protein by competitively binding to cofilin with Src family tyrosine kinase (SRC), inhibiting SRC-mediated tyrosine phosphorylation of cofilin, thereby suppressing the ubiquitination pathway degradation of cofilin. GILT overexpression stabilized and increased the protein level of cofilin in PCa cells and promoted the metastasis of PCa cells by accelerating actin dynamics through cofilin-mediated actin severing. Our findings reveal a novel mechanism of GILT in PCa and provide a new potential target for the diagnosis and treatment of PCa patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"10"},"PeriodicalIF":6.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A.","authors":"Xiuxia Wang, Yating Yang, Xianyu Zhou, Shun Yu, Xusong Luo, Lin Lu, Zhen Gao, Jun Yang","doi":"10.1038/s41420-024-02257-z","DOIUrl":"https://doi.org/10.1038/s41420-024-02257-z","url":null,"abstract":"<p><p>Keloid is benign skin tumor, and their curing is relatively difficult due to the unclear mechanism of formation. Inducing ferroptosis of keloid fibroblasts (KFs) may become a new method for treating keloid. Here, we discover interferon (IFN)γ could induce KFs ferroptosis through inhibiting SPOC domain-containing protein 1 (SPOCD1), serving as a mode of action for CD8⁺T cell (CTL)-mediated keloid killing. Mechanistically, keloid IFNγ deficiency in combination with reduced DNMT3A increase the expression of SPOCD1, thereby promoting KFs' proliferation and inhibiting its ferroptosis. Moreover, keloid SPOCD1 deficiency attenuates KFs progression and extracellular matrix (ECM) deposition. Reducing IFNγ and SPOCD1 simultaneously can increase the positive rate of reactive oxygen species (ROS) and promote mitochondrial shrinkage. Ex-vivo explant keloid culture has also confirmed that the reduction of SPOCD1 helps to reduce the proliferation rate of KFs, inhibit the angiogenesis of keloid scars, and thus inhibit keloid formation. Thus, IFNγ signaling paired with SPOCD1 is a natural keloid ferroptosis promoting mechanism and a mode of action of CTLs. Targeting SPOCD1 pathway is a potential anti-keloid approach.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"9"},"PeriodicalIF":6.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}