Cell Death & Disease最新文献

{"title":"Role of the androgen receptor in melanoma aggressiveness.","authors":"Marzia Di Donato, Costanza Maria Cristiani, Mariaelena Capone, Cinzia Garofalo, Gabriele Madonna, Lucia Carmela Passacatini, Margaret Ottaviano, Paolo Antonio Ascierto, Ferdinando Auricchio, Ennio Carbone, Antimo Migliaccio, Gabriella Castoria","doi":"10.1038/s41419-025-07350-4","DOIUrl":"https://doi.org/10.1038/s41419-025-07350-4","url":null,"abstract":"<p><p>Malignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall survival and long-term disease containment. Nevertheless, the disease often progresses and becomes resistant to the therapies. As such, the discovery of new targets and drugs for advanced melanoma still remains a difficult task. Gender disparities, with a female advantage in melanoma incidence and outcome, have been reported. Although emerging studies support the pro-tumorigenic role of androgen/androgen receptor axis in melanoma, the molecular bases of such evidence are still under intense investigation. We now report that ligand activation of the androgen receptor drives melanoma invasiveness and its escape from natural killer-mediated cytotoxic effect. By combining different experimental approaches, we observe that melanoma escape is mediated by the androgen-triggered shedding of the surface molecule MICA. Specific blockade of ADAM10 or androgen receptor impairs the androgen-induced MICA shedding and melanoma immune-escape. Further, the increase in MICA serum levels correlates with a poor outcome in melanoma patients treated with the anti-PD-1 monoclonal antibody, pembrolizumab. At last, melanoma cells depleted of the androgen receptor become more responsive to the most commonly used immunocheckpoint inhibitors, suggesting that the receptor dampens the immunotherapy efficacy. Taken together, our findings identify the androgen receptor as a diagnostic guidance in melanoma and support the repositioning of AR blockers in clinical management of patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"34"},"PeriodicalIF":8.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCDH17 induces colorectal cancer metastasis by destroying the vascular endothelial barrier.","authors":"Fengyun Dong, Pinghui Zhou, Feifei Kong, Sijie Cao, Xiaozao Pan, Shujing Cai, Xinke Chen, Sen Wang, Na Li, Baoyu He, Rou Zhao, Bin Zhang, Qingli Bie","doi":"10.1038/s41419-025-07355-z","DOIUrl":"https://doi.org/10.1038/s41419-025-07355-z","url":null,"abstract":"<p><p>Compromised vascular integrity facilitates the cancer cells extravasation and metastasis. However, the mechanisms leading to a disruption in vascular integrity in colorectal cancer (CRC) remain unclear. In this study, PCDH17 expression was higher in the vascular endothelial cells of colon cancer with distant metastasis, and the rates of PCDH17⁺ endothelial cells (ECs) was associated with the M stage in clinical pathological characteristics analysis and correlated with a poor survival prognosis. The liver and lung metastatic dissemination of MC-38 was significantly decreased in PCDH17^-/-mice. The ubiquitination and degradation of VEGFR2 was prevented by the interaction between PCDH17 and the E3 ubiquitin ligase MARCH5, which causing the separation of internalized VE-cadherin, and increased the vascular permeability and metastasis of CRC. These results highlight the importance of PCDH17 in maintaining vascular integrity, which has emphasis for endothelial barrier function in metastatic cancer. PCDH17 has the potential to be a marker for predicting tumor metastasis as well as a viable treatment target for CRC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"36"},"PeriodicalIF":8.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors.","authors":"Jennifer Wagner, David Vredevoogd, Xin Yu, Dong Lu, Daniel S Peeper, Heike M Hermanns, Jin Wang, Harald Wajant, Daniela Siegmund","doi":"10.1038/s41419-024-07325-x","DOIUrl":"https://doi.org/10.1038/s41419-024-07325-x","url":null,"abstract":"<p><p>This study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death receptor-induced necroptosis and in one cell line (D10) a mild sensitization for TNFR1-induced apoptosis. TRAF2 deficiency inhibited death receptor-induced classical NFκB-mediated production of IL-8 only in a subset of cell lines and only partly. TRAF5, furthermore, failed to improve DR-induced NFκB signaling in HCT116-PIK3CAmut and HCT116-PIK3CAmut-TRAF2_KO cells. These findings argue for a non-obligatory role of TRAF2 in death receptor-induced classical NFκB signaling. Similar as in TRAF2-deficient cells, TNF- and CD95L-induced NFκB signaling was found to be only poorly affected in RIPK1_KO cells and in cells treated with the RIPK1-specific PROTAC LD4172. Intriguingly, however, death receptor-induced NFκB signaling was completely inhibited in HCT116-PIK3CAmut cells double deficient for TRAF2 and RIPK1 and in TRAF2-deficient cells treated with LD4172. Moreover, with exception of recruitment of TRADD, acting upstream to TRAF2 and parallel to RIPK1, TNFR1 signaling complex formation was abrogated in TRAF2-RIPK1 DKO cells. Based on our findings, two distinguishable types of TNFR1-interacting complexes promote TNF-induced NFκB signaling: First, a TRADD-TRAF2/cIAP utilizing complex Ia which becomes evident in RIPK1-deficient cells. Second, a non-modified RIPK1 utilizing complex Ib which acts in TRADD- or TRAF2-deficient cells. Complex Ia and Ib may furthermore interact and cooperate to ubiquitinate RIPK1 resulting in a modified complex Ia/b preventing complex Ia and Ib to convert to the established TNFR1-induced cytotoxic complexes IIa and IIb.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"35"},"PeriodicalIF":8.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Adipose-derived mesenchymal stromal cells promote corneal wound healing by accelerating the clearance of neutrophils in cornea.","authors":"Qianwen Shang, Yunpeng Chu, Yanan Li, Yuyi Han, Daojiang Yu, Rui Liu, Zhiyuan Zheng, Lin Song, Jiankai Fang, Xiaolei Li, Lijuan Cao, Zheng Gong, Liying Zhang, Yongjing Chen, Ying Wang, Changshun Shao, Yufang Shi","doi":"10.1038/s41419-024-07295-0","DOIUrl":"https://doi.org/10.1038/s41419-024-07295-0","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"32"},"PeriodicalIF":8.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Binding of carbon nanotube to BMP receptor 2 enhances cell differentiation and inhibits apoptosis via regulating bHLH transcription factors.","authors":"Y Zhang, Q Mu, H Zhou, K Vrijens, M F Roussel, G Jiang, B Yan","doi":"10.1038/s41419-024-07291-4","DOIUrl":"https://doi.org/10.1038/s41419-024-07291-4","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"33"},"PeriodicalIF":8.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis.","authors":"Panpan Lian, Li Li, Renwei Lu, Bin Zhang, Junaid Wazir, Chaode Gu, Bojie Ma, Wenyuan Pu, Wangsen Cao, Zhiqiang Huang, Zhonglan Su, Hongwei Wang","doi":"10.1038/s41419-025-07358-w","DOIUrl":"https://doi.org/10.1038/s41419-025-07358-w","url":null,"abstract":"<p><p>Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the sustained STAT3 activation remain poorly understood. Here, we identify sphingosine-1-phosphate receptor 3 (S1PR3) as a critical regulator of STAT3 activation and psoriasis pathogenesis, orchestrating a self-amplifying circuit that sustains keratinocyte hyperproliferation and chronic inflammation. S1PR3 expression is markedly elevated in psoriatic lesions and correlates with disease severity. Using genetic and pharmacological approaches, we reveal a novel S1PR3-Src-STAT3 signaling axis that drives both early and prolonged STAT3 activation in keratinocytes. Mechanistically, S1PR3 operates through Gαi/PKA-mediated Src activation, enhancing STAT3 phosphorylation and subsequent transcriptional activity. Importantly, we reveal a previously unrecognized positive feedback loop wherein activated STAT3 directly upregulates S1PR3 expression, perpetuating inflammation and hyperproliferation. Genetic deletion of S1pr3 in mice or pharmacological inhibition of S1PR3 significantly attenuates psoriasis-like skin inflammation, decreasing epidermal hyperplasia, dermal angiogenesis, and inflammatory mediator production. These findings provide new insights into the molecular mechanisms underlying psoriasis and identify S1PR3 as a promising therapeutic target. Our study suggests that disrupting the S1PR3-STAT3 feedback loop may offer a novel strategy for treating psoriasis and potentially other chronic inflammatory diseases driven by persistent STAT3 activation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"31"},"PeriodicalIF":8.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting estrogen-regulated system x_c^- promotes ferroptosis and endocrine sensitivity of ER+ breast cancer.","authors":"Jiawei Cao, Tong Zhou, Tao Wu, Rixu Lin, Ju Huang, Dejin Shi, Jiawei Yu, Yinrui Ren, Changrui Qian, Licai He, Guang Wu, Zhixiong Dong, Shaofei Yuan, Haihua Gu","doi":"10.1038/s41419-025-07354-0","DOIUrl":"https://doi.org/10.1038/s41419-025-07354-0","url":null,"abstract":"<p><p>Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of cases. Endocrine therapies targeting estrogen are the first line therapies for ER+ breast cancer. However, resistance to these therapies occurs in about half of patients, leading to decreased survival rates. Inducing ferroptosis is a promising therapeutic strategy for cancer treatment for refractory and malignant cancers including triple-negative breast cancer. Nevertheless, ER+ breast cancer is relatively resistant to ferroptosis inducers. Here, we uncovered that ERα suppressed ferroptosis in ER+ breast cancer. Silencing ERα triggered ferroptosis, which was attenuated by ferroptosis inhibitor Ferrostatin-1, and was enhanced by ferroptosis inducer Erastin. Mechanistically, ERα transcriptionally upregulated the expression of SLC7A11 and SLC3A2, two subunits of the system x_c^-, which is one key inhibitory regulator of ferroptosis. Overexpression of the exogenous SLC7A11 and SLC3A2 was able to mitigate ferroptosis induced by ERα inhibition. Moreover, SLC7A11 and SLC3A2 levels were elevated in endocrine-resistant breast cancer cells and tumors. Importantly, the system x_c^- inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"30"},"PeriodicalIF":8.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ApoM maintains cellular homeostasis between mitophagy and apoptosis by affecting the stability of Nnt mRNA through the Zic3-ApoM-Elavl2-Nnt axis during neural tube closure.","authors":"Qing Liu, Dan Liu, Yuejiao Wang, Xiaowei Wei, Wei Ma, Hui Gu, Shanshan Jia, Yiwen He, Wenting Luo, Songying Cao, Zhonghua Yang, Anhua Wu, Zhengwei Yuan","doi":"10.1038/s41419-025-07343-3","DOIUrl":"https://doi.org/10.1038/s41419-025-07343-3","url":null,"abstract":"<p><p>Research on the aetiology of neural tube defects (NTDs) has made progress in recent years. However, the molecular mechanism of apolipoproteins underlying NTDs development remains unclear. This study aimed to investigate the function of apolipoprotein M (ApoM) in the pathogenesis of NTDs and its underlying mechanisms. We demonstrated that ApoM expression was reduced in the spinal cord samples of rat models and human fetuses with NTDs respectively. Specifically, lack of ApoM resulted in reduced cytosolic localization of Elavl2 and caused Nnt mRNA degradation, which further led to impaired cell homeostasis by suppressing PINK1-PRKN-mediated mitophagy and promoting apoptosis and subsequent NTDs formation. Moreover, Zic3 directly interacted with the promoter of ApoM and activated its transcription. Lastly, intra-amniotic delivery of adenoviral recombinant Zic3 or ApoM could promote mitophagy and alleviate apoptosis in spinal cords of NTDs. Collectively, these findings highlight the important role of the Zic3-ApoM-Elavl2-Nnt axis in cellular homeostasis during neural tube development, thereby revealing an intracellular molecular regulatory mechanism of ApoM, providing a mechanistic basis for understanding embryonic neural development, and offering experimental evidence for potential therapeutic targets for NTDs.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"29"},"PeriodicalIF":8.1,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001075","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":"Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells.","authors":"Zheng Zhang, Huaxiang Xu, Junyi He, Qiangsheng Hu, Yuxin Liu, Zijin Xu, Wenhui Lou, Wenchuan Wu, Lei Zhang, Ning Pu, Chenye Shi, Yaolin Xu, Wenquan Wang, Liang Liu","doi":"10.1038/s41419-025-07330-8","DOIUrl":"https://doi.org/10.1038/s41419-025-07330-8","url":null,"abstract":"<p><p>As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domain-containing 7 (FBW7) inhibited the migration and proliferation of pancreatic cancer cells through its substrate c-Myc. We further found that another key substrate of FBW7, KLF5, could inhibit ferroptosis. Inhibiting KLF5 significantly enhances the cytotoxicity of oxaliplatin rather than other chemotherapy drugs. Mechanistically, we found that KLF5 inhibited the expression of heme oxygenase 1 (HMOX1) via repressing zinc finger E-box-binding homeobox 1 (ZEB1). Inhibition of KLF5 facilitated the cytotoxic effect of oxaliplatin via promoting ferroptosis. Oxaliplatin combined with KLF5 inhibitor significantly potentiated cell death in vitro and inhibited tumor growth in vivo compared with either treatment alone. These results reveal a critical role of KLF5 in sensitized chemotherapy of pancreatic cancer, and suggest that ferroptosis combined with platinum-based chemotherapy rather than gemcitabine-based chemotherapy is expected to bring better therapeutic effects.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"28"},"PeriodicalIF":8.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001080","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":"ERG mediates the differentiation of hepatic progenitor cells towards immunosuppressive PDGFRα⁺ cancer-associated fibroblasts during hepatocarcinogenesis.","authors":"Haoran Bai, Xinyu Zhu, Lu Gao, Shiyao Feng, Hegen Li, Xiaoqiang Gu, Jiahua Xu, Chen Zong, Xiaojuan Hou, Xue Yang, Jinghua Jiang, Qiudong Zhao, Lixin Wei, Li Zhang, Zhipeng Han, Wenting Liu, Jianxin Qian","doi":"10.1038/s41419-024-07270-9","DOIUrl":"https://doi.org/10.1038/s41419-024-07270-9","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) play important roles in the occurrence and development of hepatocellular carcinoma (HCC) and are a key component of the immunosuppressive microenvironment. However, the origin of CAFs has not been fully elucidated. We employed single-cell sequencing technology to identify the dynamic changes in different subsets of fibroblasts at different time points in rat primary HCC model. Inflammation-associated CAFs (Pdgfrα⁺ CAFs) were subsequently identified, which demonstrated a significant correlation with the survival duration of HCC patients and a dual role in the tumour microenvironment (TME). On the one hand, they secrete the chemokines CCL3 and CXCL12, which recruit macrophages to the tumour site. On the other hand, they produce TGFβ, inducing the polarization of these macrophages towards an immunosuppressive phenotype. According to the in vitro and in vivo results, hepatic progenitor cells (HPCs) can aberrantly differentiate into PDGFRα⁺ CAFs upon stimulation with inflammatory cytokine. This differentiation is mediated by the activation of the MAPK signaling pathway and the downstream transcription factor ERG via the TLR4 receptor. Downregulating the expression of ERG in HPCs significantly reduces the number of PDGFRα⁺ CAFs and the infiltration of tumour-associated macrophages in HCC, thereby suppressing hepatocarcinogenesis. Collectively, our findings elucidate the distinct biological functions of PDGFRα⁺ cancer-associated fibroblasts (PDGFRα⁺ CAFs) within the TME. These insights contribute to our understanding of the mechanisms underlying the establishment of an immunosuppressive microenvironment in HCC, paving the way for the exploration of novel immunotherapeutic strategies tailored for HCC treatment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"26"},"PeriodicalIF":8.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001078","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}