Cell Death & Disease最新文献

{"title":"SPOP-mediated K27-linked non-degradative ubiquitination of KCNN3 suppressing HCC progression via the CTCF-SATB1 axis.","authors":"Ziqing Zhan, Yidong Ge, Jiaxin Shi, Hongze Liang, Yuxuan Li, Jiabei Jin, Gun Chen, Fengguang Zhai, Lili Kong, Yan Lin, Siyuan Wang, Litao Chen, Linlin Liu, Kuihao Chen, Pengrong Lou, Meng Ye, Xiaofeng Jin","doi":"10.1038/s41419-026-08765-3","DOIUrl":"https://doi.org/10.1038/s41419-026-08765-3","url":null,"abstract":"<p><p>The metastasis of hepatocellular carcinoma (HCC) cells remains a major obstacle to achieving favorable clinical outcomes, yet the underlying molecular mechanisms are still not fully understood. The dysregulation of ion channels is related to epithelial-mesenchymal transition (EMT) phenotype-related pathways, especially the aberrant function of K+ ion channels in HCC. In this study, we observed that the potassium-calcium-activated channel subfamily N member 3 (KCNN3/SK3/ KCa2.3) ion channels were significantly upregulated in HCC cells, promoting the migration and invasion of HCC in vitro and in vivo. Mechanistically, activation of the KCNN3 ion channel was found to enhance phosphorylation of the CCCTC-binding factor (CTCF), which in turn stimulates transcription of the EMT-related factor special AT-rich sequence-binding protein 1 (SATB1) via binding the \"CCCTC\" region within its promoter, thereby driving HCC cell migration and invasion. Furthermore, we identified that speckle-type POZ protein (SPOP), an E3 ligase adaptor, recognizes the SPOP-binding consensus (SBC) motif \"ASSTT\" (aa 250-254) in KCNN3 and mediates its ubiquitination via K27-linked ubiquitin chain. Notably, this type of ubiquitination does not induce KCNN3 turnover, but induced KCNN3 translocation from the cell membrane into the cytosol, thus suppressing KCNN3-mediated ion channel activity. Importantly, HCC-associated SPOP mutations or KCNN3-ΔSBC dramatically disrupt the SPOP-KCNN3 regulatory axis, accelerating HCC progression. These effects can be effectively counteracted by treatment with the KCNN3 channel inhibitor edelfosine and the calcium chelators BAPTA-AM, suggesting a promising therapeutic strategy for HCC patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863703","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":"EMILIN1 emerges as a TGFβ/SETDB1-regulated secreted biomarker in Duchenne muscular dystrophy.","authors":"Maeva Zamperoni, Laura Muraine, Minh-Y Tran, Alice Granados, Anne Bigot, Valentin Petit, Mona Bensalah, Jessica Ohana, Véronique Legros, Ekaterina Boyarchuk, Johanna Bruce, Guillaume Chevreux, Véronique Joliot, Elisa Negroni, Maryline Moulin, Capucine Trollet, Slimane Ait-Si-Ali","doi":"10.1038/s41419-026-08825-8","DOIUrl":"https://doi.org/10.1038/s41419-026-08825-8","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is an incurable muscle-wasting disorder characterized by chronic membrane damage, inflammation, and progressive fibrosis. Fibrosis in DMD is driven by sustained TGFβ signaling, which promotes extracellular matrix (ECM) accumulation. We previously showed that SETDB1 sustains the TGFβ-induced fibrotic response in DMD myotubes. Here, we further show that SETDB1 modulates the TGFβ-induced secretome, particularly by regulating ECM-related proteins. Comparison of the basal secretome from DMD patient-derived myotubes and healthy controls revealed a distinct disease-specific profile. Integrating both secretome analyses, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle, as a robust shared candidate; EMILIN1 is enriched in the DMD secretome, further upregulated by TGFβ, and downregulated upon SETDB1 depletion. We confirmed EMILIN1 overexpression in DMD patient muscle biopsies, validating its pathological relevance. Functionally, EMILIN1 depletion modulated myogenic differentiation and reduced expression of the fibrotic marker SERPINE1. These findings establish EMILIN1 as a novel secreted regulator of myogenesis and fibrosis, and implicate SETDB1 in shaping the TGFβ-dependent secretome in DMD. Our integrative proteomic approach provides new insights into the molecular drivers of impaired regeneration in DMD and highlights potential therapeutic targets.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863583","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 new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury dynamically regulating mitochondrial function to remodel the immune network.","authors":"Lizheng Huang, Yuqian Wang, Chunyi Li, Xiaojing Wang, Anqi Xiao, Fanglei Han, Jinlan Jiang","doi":"10.1038/s41419-026-08834-7","DOIUrl":"https://doi.org/10.1038/s41419-026-08834-7","url":null,"abstract":"<p><p>Cerebral Ischemia-Reperfusion Injury (CIRI) is a common pathological process in ischemic stroke. Its core detriment lies in the cascade of subsequent injuries triggered by blood flow restoration after cerebrovascular recanalization, primarily including oxidative stress burst, calcium overload, immune-inflammatory imbalance, and mitochondrial dysfunction, ultimately leading to massive neuronal apoptosis and necrosis. Mitochondria, as central hubs of cellular energy metabolism and apoptosis regulation, exhibit functional disturbances that represent the initiating and core link in CIRI. CIRI triggers complex remodeling of the immune network. This dysregulated immune-inflammatory response forms a vicious cycle with mitochondrial dysfunction, exacerbating brain tissue damage. Mesenchymal Stem Cells (MSCs) and their derivatives have demonstrated significant potential in treating CIRI due to their potent paracrine and immunomodulatory functions. MSCs can repair neuronal functional basis by enhancing mitochondrial biogenesis, improving energy metabolism, inhibiting mitochondrial pathway-mediated apoptosis, restoring dynamic balance, and promoting normal mitophagy. Although existing reviews have explored the role of MSCs or mitochondrial function in CIRI, few studies have systematically integrated the bidirectional regulatory relationship between dynamic mitochondrial function and immune network remodeling. Furthermore, an in-depth analysis of the temporal therapeutic effects of MSCs and their derivatives across different pathological stages of CIRI is lacking. To address this gap, this review proposes a therapeutic strategy: MSCs exert synergistic neuroprotective effects by improving mitochondrial function through multiple targets while systematically reshaping the imbalanced immune network. This review summarizes the latest evidence regarding the temporal therapeutic role of MSCs via the \"immune-mitochondrial\" axis at different stages of CIRI. It elucidates the pivotal role of mitochondria as a central hub connecting metabolic crisis and immune storm, and untangles novel mechanisms such as MSC-mediated mitochondrial transfer and immune cell metabolic reproprogramming, providing a theoretical foundation for developing novel stroke therapies based on cell therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834276","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":"MECP2 mutations disrupt pluripotent stem cell fate through remodeling of the three-dimensional genome.","authors":"Jing Zhou, Yizhuo Che, Xintao Jing, Fang Li, Hang Peng, Yuchun Liu, Li Cao, Jinyuan Zhang, Xiaofei Wang, Jia Zhang, Aihong Guo, Dongdong Tong, Bingju Wang, Chen Huang","doi":"10.1038/s41419-026-08837-4","DOIUrl":"https://doi.org/10.1038/s41419-026-08837-4","url":null,"abstract":"<p><p>Mutations in the MECP2 gene are the primary cause of Rett syndrome, yet their mechanistic roles during early developmental stages remain poorly understood. In this study, CRISPR-Cas9 technology was applied to generate three loss-of-function mutations in male induced pluripotent stem cells (iPSCs), namely MECP2^del6, MECP2^insA, and MECP2^insT, each targeting distinct functional domains of MECP2. Our results showed that MECP2 mutations led to reduced proliferative capacity and impaired embryoid body formation in iPSCs, and caused premature loss of OCT4 expression during embryoid body development. To explore the molecular mechanisms in depth, we performed integrated multi-omics analyses. MECP2 mutations remodeled three-dimensional genome organization by disrupting chromatin compartmentalization, destabilizing topologically associated domain boundaries, and redistributing frequent interaction hotspots and super-hotspots linked to genes involved in development and chromatin remodeling. These structural alterations were accompanied by genome-wide changes in chromatin accessibility, with differentially open regions enriched for the binding motifs of pluripotency transcription factors OCT4/SOX2 and the 3D genome organizer CTCF. Further analyses confirmed that the MECP2 mutations enhanced CTCF binding at its co-binding sites. Collectively, this study systematically elucidates how MECP2 mutations interfere with iPSC fate determination by reshaping 3D genome organization and chromatin accessibility at multiple levels, providing a new perspective on the early pathogenesis of Rett syndrome.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855987","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":"Genetic mutations governing ferroptosis sensitivity and resistance: a precision approach to cancer therapy.","authors":"Peyman Tabnak, Mohammad Ebrahimnezhad, Zanyar HajiEsmailPoor","doi":"10.1038/s41419-026-08796-w","DOIUrl":"https://doi.org/10.1038/s41419-026-08796-w","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent programmed cell death pathway driven by lipid peroxidation, offers a transformative approach to cancer therapy by exploiting unique cellular vulnerabilities. This comprehensive review elucidates the intricate molecular mechanisms of ferroptosis and their modulation by genetic mutations across diverse malignancies, including lung, hematological, liver, colorectal, breast, glioma, renal, pancreatic, thyroid, prostate, cervical, gastric, and melanoma. We delineate the critical functions of ferroptosis regulators, such as GPX4, system Xc⁻, and iron metabolism proteins, in orchestrating the delicate balance between oxidative damage and antioxidant protection. The study further examines how oncogenic mutations in genes like EGFR, KRAS, TP53, KEAP1, and IDH1 reshape ferroptosis susceptibility or resistance through alterations in metabolic pathways, redox homeostasis, and tumor microenvironment interactions. By highlighting mutation-specific sensitivities, this work underscores the potential of ferroptosis-targeted strategies to surmount therapeutic resistance, synergize with conventional treatments like chemotherapy and immunotherapy, and drive precision oncology forward, paving the way for enhanced clinical outcomes across a broad spectrum of cancers.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834285","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":"OTUB2-mediated deubiquitination upregulates U2AF2 to promote colorectal cancer evasion of autophagy-ferroptosis.","authors":"Xi Chen, Yanxin Qi, Qigang Nie, Kai Zhou, Ao Mo","doi":"10.1038/s41419-026-08415-8","DOIUrl":"https://doi.org/10.1038/s41419-026-08415-8","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Ferroptosis, an iron-dependent form of programmed cell death, has emerged as a potential therapeutic target. However, the regulatory mechanisms that allow CRC cells to evade ferroptosis are not fully understood. This study focuses on OTUB2, a deubiquitinating enzyme, and its role in stabilizing U2AF2, which allows CRC cells to resist ferroptosis and autophagy. We analyzed CRC cells and clinical samples to evaluate the effects of OTUB2 on U2AF2 deubiquitination. OTUB2 knockdown and overexpression models were established in CRC cell lines (LoVo, RKO, SW480, HT115) to assess ferroptosis and autophagy activity. Various assays, including western blotting, immunoprecipitation, colony formation, and transwell migration assays, were used to evaluate cell proliferation, migration, and iron metabolism markers. In vivo xenograft models were also employed to assess tumor growth under OTUB2-U2AF2 axis disruption. OTUB2 was highly expressed in CRC tissues compared to normal controls. Knockdown of OTUB2 significantly increased ferroptosis, while enhancing autophagy. Conversely, OTUB2 overexpression reduced ferroptosis and autophagy, maintaining CRC cell survival and proliferation. In vivo studies confirmed that disrupting the OTUB2-U2AF2 axis impaired tumor growth by activating both ferroptosis and autophagy. Importantly, a reciprocal activation relationship between ferroptosis and autophagy was observed under OTUB2-U2AF2 axis deficiency. OTUB2 stabilizes U2AF2 in CRC cells, enabling them to evade ferroptosis and autophagy. Disruption of the OTUB2-U2AF2 axis activates both processes, suppressing tumor growth. Targeting this axis presents a promising therapeutic strategy for CRC treatment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834336","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":"Hippocampal Satb2 regulates the cognitive function of adult mice through pleiotrophin.","authors":"Xin-Ren Yu, Yu-Bing Wang, Zhi-Yi Tu, Ying-Ying Wang, Qiu-Xiang Chen, Pin-Xi Xie, Yuan-Yuan Yong, Yan-Yan Wang, Ting-Ting Zhang, Jia-Jun Sun, Tao Chang, Hui-Xiang Yang, Ning-Ning Song, Yu-Qiang Ding, Xuan Zhao, Lei Zhang","doi":"10.1038/s41419-026-08820-z","DOIUrl":"https://doi.org/10.1038/s41419-026-08820-z","url":null,"abstract":"<p><p>The special AT-rich sequence-binding protein 2 (SATB2) is associated with human cognitive ability. Mutations in the SATB2 gene lead to SATB2-associated syndrome (SAS), characterized by severe intellectual disability. SATB2 is mainly expressed in pyramidal neurons in the cerebral cortex and hippocampus, playing a crucial role in cognitive processes. However, the function of SATB2 in the adult hippocampus remains unclear. In this study, we deleted Satb2 in the CA1 region of the adult mouse hippocampus and observed cognitive impairments along with significant changes in soma and dendrite morphology. Additionally, we identified the growth factor pleiotrophin (PTN) as a downstream target of Satb2, essential for mediating its impact on cognitive functions. Importantly, increasing PTN expression mitigated the morphological and behavioral deficits resulting from Satb2 deletion in CA1. Our findings highlight the importance of hippocampal Satb2 in regulating cognitive function in adult mice through PTN modulation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834320","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":"Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.","authors":"Stefania Modafferi, Valentina Silenzi, Anna Garbelli, Gloria Lazoi, Eveljn Scarian, Sara D'Uva, Tiziana Santini, Adelaide Riccardi, Mauro Cozzolino, Orietta Pansarasa, Nadia D'Ambrosi, Simone Sabbioneda, Mariangela Morlando, Sofia Francia","doi":"10.1038/s41419-026-08603-6","DOIUrl":"https://doi.org/10.1038/s41419-026-08603-6","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834322","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":"Characterization of ADGRG6 as a potential molecular oncotarget of pancreatic cancer.","authors":"Qian-Hui Gu, Xiao-Ren Zhu, Jian-Zhuo Jiang, Na Liu, An-Qi Jin, Yan Zhang, Jing-Jing Lu, Ping Li, Zhen-Yu Ye, Yuan-Yuan Liu, Min-Bin Chen","doi":"10.1038/s41419-026-08766-2","DOIUrl":"https://doi.org/10.1038/s41419-026-08766-2","url":null,"abstract":"<p><p>Identifying novel therapeutic targets for pancreatic cancer (PC) is crucial for improving patient outcomes. This study identified the functions, expression, and associated mechanisms of adhesion G protein-coupled receptor G6 (ADGRG6/ GPR126) in PC. Bioinformatics analyses revealed substantial upregulation of ADGRG6 in human PC, correlating with poor survival rates and advanced tumor stages. Elevated ADGRG6 expression has been observed in human PC tissues and cell lines. Targeted depletion of ADGRG6 via the CRISPR/Cas9 knockout (KO) or lentiviral shRNA technology in established and primary PC cells (priPC-1) resulted in a substantial decrease in cell cycle progression, cell proliferation, viability, as well as reduced migratory and invasive capabilities. Conversely, ADGRG6 overexpression further enhanced the malignant behavior of PC cells. Mechanistically, ADGRG6 is crucial for Akt-mTOR cascade activation. ADGRG6 depletion markedly decreased Akt, S6, and 4E-BP1 phosphorylation. Constitutively active mutant Akt1 (S473D, caAkt1) reversed the anti-proliferative and anti-migratory effects of ADGRG65 shRNA and restored Akt-mTOR phosphorylation. Further analysis revealed that ADGRG6-driven Akt-mTOR activation is mediated by G protein inhibitory subunit 3 (Gαi3). ADGRG6 shRNA significantly inhibited subcutaneous PC xenograft growth in mice, accompanied by reduced Akt-mTOR signaling activation. In contrast, ADGRG6 overexpression promotes xenograft growth. Together, these findings establish ADGRG6 as a critical mediator of PC progression via Gαi3-dependent activation of the Akt-mTOR axis. Targeting ADGRG6 is a promising therapeutic strategy for combating PC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834302","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":"Micropeptide SCAPEP triggers lung adenocarcinoma tumorigenesis via regulating autophagy by promoting CDK15-mediated phosphorylation of vimentin.","authors":"Xuefei Shi, Qiuhui Li, Fengqi Nie, Xuting Xu, Yili Shen, Hui Shen, Kai Chen, Bin Wang, Kaihua Lu, Shunli Dong, Liu Xianghua","doi":"10.1038/s41419-026-08767-1","DOIUrl":"https://doi.org/10.1038/s41419-026-08767-1","url":null,"abstract":"<p><p>Lung adenocarcinoma is one of the most common forms of lung cancer with a low five-year survival rate. The roles of the novel proteins and peptides encoded by circular RNAs (circRNAs) in cancer are emerging. However, the functions and underlying molecular mechanisms of the peptides that affect lung adenocarcinoma progression are yet to be elucidated. In this study, we characterized a lung-adenocarcinoma-associated small peptide (SCAPEP) encoded by circRNA_0065214 via the IRES element. Tumors with a large diameter, lymphatic metastasis, or advanced stage have high SCAPEP levels. Furthermore, modulation of SCAPEP expression can regulate cell proliferation, metastasis, and autophagy in vitro or in vivo. We found that the up-regulation of methionine synthase reductase (MTRR) by regulating the phosphorylation of vimentin Ser56 in SCAPEP is a key mechanism driving the aggressiveness of SCAPEP -high lung adenocarcinoma. Consistent with these findings, MTRR overexpression reversed the effects of SCAPEP depletion. Altogether, our observations provide novel insights into how oncogenic peptides crosstalk with autophagy and contribute to lung adenocarcinoma tumorigenesis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834266","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}