Pub Date : 2025-11-07DOI: 10.1038/s41418-025-01601-9
S. L. Petersen, T. T. Chen, D. A. Lawrence, S. A. Marsters, F. Gonzalvez, A. Ashkenazi
{"title":"Correction: TRAF2 is a biologically important necroptosis suppressor","authors":"S. L. Petersen, T. T. Chen, D. A. Lawrence, S. A. Marsters, F. Gonzalvez, A. Ashkenazi","doi":"10.1038/s41418-025-01601-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01601-9","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455355","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}
Pub Date : 2025-11-04DOI: 10.1038/s41418-025-01606-4
Hayden Holmlund, Manon Coulée, Yasuhiro Yamauchi, Benazir Yarbabaeva, Muhammetnur Tekayev, Isabella R. Garcia, Olivier U. Feudjio, Alberto de la Iglesia, Lee Larcombe, Peter J. I. Ellis, Julie Cocquet, Monika A. Ward
{"title":"Correction: Large-scale transcriptomic analyses reveal downstream target genes of ZFY1 and ZFY2 transcription factors in male germ cells","authors":"Hayden Holmlund, Manon Coulée, Yasuhiro Yamauchi, Benazir Yarbabaeva, Muhammetnur Tekayev, Isabella R. Garcia, Olivier U. Feudjio, Alberto de la Iglesia, Lee Larcombe, Peter J. I. Ellis, Julie Cocquet, Monika A. Ward","doi":"10.1038/s41418-025-01606-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01606-4","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434674","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}
To prevent cell death induced by elevated oxidative stress, cancer cells activate a series of antioxidant defense mechanisms to mitigate cytotoxicity, thereby enhancing the resistance to pro-oxidative therapy. However, the underlying antioxidant mechanisms in cancer cells remain inadequately understood. Through co-immunoprecipitation followed by quantitative mass spectrometry analysis, we for the first time identified that cytoplasmic ALDH1L1 translocates into mitochondria and co-localizes with mitochondrial transcription factor TFAM in cancer cells in a ROS-dependent feedback manner. Mitochondria-translocated ALDH1L1 maintains mitochondrial redox homeostasis by producing NADPH. Moreover, our findings revealed that the ROS-mediated oxidative modification of ALDH1L1 is necessary for its interaction with HSP90β and subsequent translocation into mitochondria via TOM70, where it binds to TFAM to prevent degradation by LONP1. Furthermore, we found that mitochondrial ALDH1L1 antagonized the double-edged role of ROS in cancer cell survival, indicating that disruption of ALDH1L1 expression promoted cancer cell proliferation and autophagy but concurrently diminished cellular capacity to counteract ROS-induced apoptosis. Consistently, ALDH1L1 knockout enhanced the anti-tumor effect of low-dose pro-oxidant Elesclomol, thereby achieving better efficacy and safety of pro-oxidant therapy. Furthermore, our results demonstrated that the combination of Elesclomol with HSP90 inhibitor Ganetespib exhibited synergistic anti-tumor effects. In conclusion, our findings that mitochondria-translocated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy can provide critical insights into developing effective pro-oxidative therapies against tumors.
{"title":"Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy","authors":"Dan Wu, Xin Zhao, Caiyu Shi, Jing Zhao, Zeyu Yan, Runjiao Zhang, Xianchun Lan, Jiaze An, Qichao Huang, Xianli He, Tingting Ren, Jinliang Xing","doi":"10.1038/s41418-025-01604-6","DOIUrl":"https://doi.org/10.1038/s41418-025-01604-6","url":null,"abstract":"To prevent cell death induced by elevated oxidative stress, cancer cells activate a series of antioxidant defense mechanisms to mitigate cytotoxicity, thereby enhancing the resistance to pro-oxidative therapy. However, the underlying antioxidant mechanisms in cancer cells remain inadequately understood. Through co-immunoprecipitation followed by quantitative mass spectrometry analysis, we for the first time identified that cytoplasmic ALDH1L1 translocates into mitochondria and co-localizes with mitochondrial transcription factor TFAM in cancer cells in a ROS-dependent feedback manner. Mitochondria-translocated ALDH1L1 maintains mitochondrial redox homeostasis by producing NADPH. Moreover, our findings revealed that the ROS-mediated oxidative modification of ALDH1L1 is necessary for its interaction with HSP90β and subsequent translocation into mitochondria via TOM70, where it binds to TFAM to prevent degradation by LONP1. Furthermore, we found that mitochondrial ALDH1L1 antagonized the double-edged role of ROS in cancer cell survival, indicating that disruption of ALDH1L1 expression promoted cancer cell proliferation and autophagy but concurrently diminished cellular capacity to counteract ROS-induced apoptosis. Consistently, ALDH1L1 knockout enhanced the anti-tumor effect of low-dose pro-oxidant Elesclomol, thereby achieving better efficacy and safety of pro-oxidant therapy. Furthermore, our results demonstrated that the combination of Elesclomol with HSP90 inhibitor Ganetespib exhibited synergistic anti-tumor effects. In conclusion, our findings that mitochondria-translocated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy can provide critical insights into developing effective pro-oxidative therapies against tumors.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"152 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434676","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}
Pub Date : 2025-11-01DOI: 10.1038/s41418-025-01603-7
Jose C. Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R. Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh
The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPR ER ) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPR ER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans , increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPR ER activation were dependent on PERK signalling and its interaction with the UPR mt . The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.
{"title":"Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly","authors":"Jose C. Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R. Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh","doi":"10.1038/s41418-025-01603-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01603-7","url":null,"abstract":"The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPR <jats:sup>ER</jats:sup> ) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPR <jats:sup>ER</jats:sup> signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of <jats:italic>C. elegans</jats:italic> embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and <jats:italic>C. elegans</jats:italic> , increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult <jats:italic>C. elegans</jats:italic> resulted in a maladaptive response. In both models the adaptations to UPR <jats:sup>ER</jats:sup> activation were dependent on PERK signalling and its interaction with the UPR <jats:sup>mt</jats:sup> . The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145423992","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}
In the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), the emergence of acquired resistance remains a significant challenge. Elucidating the underlying mechanisms of resistance is crucial for developing novel strategies to overcome or delay therapeutic escape. To this end, this study aimed to identify key drivers of EGFR-TKIs resistance and explore actionable targets for intervention. We investigated resistance mechanisms by integrating CRISPR/Cas9-based genome-wide screening with tandem mass tag (TMT) proteomic analysis, and virtually screened bioactive small molecule libraries to identify compounds capable of restoring EGFR-TKIs sensitivity. The multi-omics approach revealed that CCT2 is a critical mediator of resistance to third-generation EGFR-TKIs in lung cancer, with higher expression of CCT2 observed in resistant cells compared to sensitive cells. Mechanistically, CCT2 recruits tripartite motif-containing protein 28 (TRIM28) to catalyze SUMO2 modification of thioredoxin-related transmembrane protein 1 (TMX1), inhibiting its ubiquitination and enhancing protein stability. This post-translational modification (PTM) promotes TMX1-dependent reactive oxygen species (ROS) clearance, thereby conferring resistance. Importantly, pharmacological inhibition with the compound HY-10127, identified through virtual screening, effectively restored EGFR-TKIs sensitivity in resistant cell lines and delayed the development of resistance in xenograft models. The findings establish the CCT2/TRIM28/TMX1/ROS axis as a novel resistance mechanism in EGFR-mutated lung cancer, and targeting this pathway with HY-10127 represents a promising strategy to overcome resistance to third-generation EGFR-TKIs, providing preclinical rationale for clinical translation. These discoveries advance our understanding of molecular resistance mechanisms and offer potential therapeutic targets for improving lung cancer prognosis.
在使用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）治疗非小细胞肺癌（NSCLC）时，获得性耐药的出现仍然是一个重大挑战。阐明耐药性的潜在机制对于开发克服或延迟治疗逃逸的新策略至关重要。为此，本研究旨在确定EGFR-TKIs耐药的关键驱动因素，并探索可操作的干预靶点。我们通过整合基于CRISPR/ cas9的全基因组筛选和串联质量标签（TMT）蛋白质组学分析来研究耐药机制，并通过虚拟筛选生物活性小分子文库来鉴定能够恢复EGFR-TKIs敏感性的化合物。多组学方法显示，CCT2是肺癌对第三代EGFR-TKIs耐药的关键介质，与敏感细胞相比，CCT2在耐药细胞中的表达更高。机制上，CCT2招募TRIM28 (tripartite motif-containing protein 28)，催化SUMO2修饰硫氧还蛋白相关跨膜蛋白1 (TMX1)，抑制其泛素化，增强蛋白稳定性。这种翻译后修饰（PTM）促进tmx1依赖的活性氧（ROS）清除，从而赋予耐药性。重要的是，通过虚拟筛选确定的化合物HY-10127的药理抑制作用，有效地恢复了耐药细胞系中EGFR-TKIs的敏感性，并延缓了异种移植模型中耐药的发展。研究结果表明，CCT2/TRIM28/TMX1/ROS轴是egfr突变肺癌的一种新的耐药机制，HY-10127靶向这一途径是克服第三代EGFR-TKIs耐药的一种有希望的策略，为临床转化提供了临床前依据。这些发现促进了我们对分子耐药机制的理解，并为改善肺癌预后提供了潜在的治疗靶点。
{"title":"CRISPR/Cas9 library screening uncovered CCT2 as a critical driver of acquired resistance to EGFR-targeted therapy by stabilizing TMX1 in non-small cell lung cancer","authors":"Zihao Ke, Qi Zhang, Xingyu Chen, Rongrong Jin, Gaohua Han, Qianhua Cao, Ke Zhu, Shihui Wei, Jiajin Chen, Qian Wang, Meiling Zhang, Weina Huang, Kaimin Li, Kunlong Xiong, Kaihua Lu, Ying Chen, Chao Cao","doi":"10.1038/s41418-025-01600-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01600-w","url":null,"abstract":"In the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), the emergence of acquired resistance remains a significant challenge. Elucidating the underlying mechanisms of resistance is crucial for developing novel strategies to overcome or delay therapeutic escape. To this end, this study aimed to identify key drivers of EGFR-TKIs resistance and explore actionable targets for intervention. We investigated resistance mechanisms by integrating CRISPR/Cas9-based genome-wide screening with tandem mass tag (TMT) proteomic analysis, and virtually screened bioactive small molecule libraries to identify compounds capable of restoring EGFR-TKIs sensitivity. The multi-omics approach revealed that CCT2 is a critical mediator of resistance to third-generation EGFR-TKIs in lung cancer, with higher expression of CCT2 observed in resistant cells compared to sensitive cells. Mechanistically, CCT2 recruits tripartite motif-containing protein 28 (TRIM28) to catalyze SUMO2 modification of thioredoxin-related transmembrane protein 1 (TMX1), inhibiting its ubiquitination and enhancing protein stability. This post-translational modification (PTM) promotes TMX1-dependent reactive oxygen species (ROS) clearance, thereby conferring resistance. Importantly, pharmacological inhibition with the compound HY-10127, identified through virtual screening, effectively restored EGFR-TKIs sensitivity in resistant cell lines and delayed the development of resistance in xenograft models. The findings establish the CCT2/TRIM28/TMX1/ROS axis as a novel resistance mechanism in EGFR-mutated lung cancer, and targeting this pathway with HY-10127 represents a promising strategy to overcome resistance to third-generation EGFR-TKIs, providing preclinical rationale for clinical translation. These discoveries advance our understanding of molecular resistance mechanisms and offer potential therapeutic targets for improving lung cancer prognosis.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"58 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404898","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":"A STING for necroptosis","authors":"Marlena Nastassja Schlecht, Karolin Flade, Wulf Tonnus","doi":"10.1038/s41418-025-01602-8","DOIUrl":"https://doi.org/10.1038/s41418-025-01602-8","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381938","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}
Pub Date : 2025-10-27DOI: 10.1038/s41418-025-01597-2
Qian Wang, Rayman T N Tjokrodirijo, Hailiang Mei, Peter A van Veelen, Peter Ten Dijke, Chuannan Fan
Transforming growth factor (TGF)-β signaling is a key driver to induce epithelial-to-mesenchymal transition (EMT), a process that enhances cancer cell plasticity and metastatic potential. However, the role of circular RNAs (circRNAs) in TGF-β signaling remains largely unexplored. Here, we identify circTGFBR2(3-6), a circRNA derived from TGF-β receptor 2 (TGFBR2) pre-mRNA, as a critical enhancer of TGF-β/SMAD signaling in breast cancer cells. Depletion of circTGFBR2(3-6) inhibits TGF-β-induced EMT, cell migration, and in vivo extravasation of breast cancer cells. Mechanistically, circTGFBR2(3-6) acts as a scaffold that facilitates the interaction between the RNA-binding protein insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and TGF-β receptor 1 (TGFBR1) mRNA in an N6-methyladenosine (m6A)-dependent manner, and thereby stabilizes TGFBR1 mRNA and promotes its expression. Furthermore, IGF2BP3 knockdown reduces circTGFBR2(3-6)-mediated enhancement of TGF-β/SMAD signaling, as well as TGF-β-induced EMT and cell migration. Our findings identify circTGFBR2(3-6) as a novel potentiator of TGF-β/SMAD signaling at the receptor level and highlight IGF2BP3 as a critical m6A reader that mediates circTGFBR2(3-6)-driven breast cancer cell plasticity.
{"title":"circTGFBR2(3-6) acts as an assembly platform for RNA-binding protein IGF2BP3 and TGFBR1 mRNA to enhance breast cancer cell plasticity.","authors":"Qian Wang, Rayman T N Tjokrodirijo, Hailiang Mei, Peter A van Veelen, Peter Ten Dijke, Chuannan Fan","doi":"10.1038/s41418-025-01597-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01597-2","url":null,"abstract":"<p><p>Transforming growth factor (TGF)-β signaling is a key driver to induce epithelial-to-mesenchymal transition (EMT), a process that enhances cancer cell plasticity and metastatic potential. However, the role of circular RNAs (circRNAs) in TGF-β signaling remains largely unexplored. Here, we identify circTGFBR2(3-6), a circRNA derived from TGF-β receptor 2 (TGFBR2) pre-mRNA, as a critical enhancer of TGF-β/SMAD signaling in breast cancer cells. Depletion of circTGFBR2(3-6) inhibits TGF-β-induced EMT, cell migration, and in vivo extravasation of breast cancer cells. Mechanistically, circTGFBR2(3-6) acts as a scaffold that facilitates the interaction between the RNA-binding protein insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and TGF-β receptor 1 (TGFBR1) mRNA in an N<sup>6</sup>-methyladenosine (m<sup>6</sup>A)-dependent manner, and thereby stabilizes TGFBR1 mRNA and promotes its expression. Furthermore, IGF2BP3 knockdown reduces circTGFBR2(3-6)-mediated enhancement of TGF-β/SMAD signaling, as well as TGF-β-induced EMT and cell migration. Our findings identify circTGFBR2(3-6) as a novel potentiator of TGF-β/SMAD signaling at the receptor level and highlight IGF2BP3 as a critical m<sup>6</sup>A reader that mediates circTGFBR2(3-6)-driven breast cancer cell plasticity.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376233","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}
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