Cell Death Discovery最新文献

{"title":"N6-methyladenosine modification of MEF2A weakens cetuximab sensitivity in colorectal cancer via PD-L1/SOX12 axis.","authors":"Cao Gao, Jiajia He, Jiemin Zhao, Xuefeng Ni, Yanjie Xu","doi":"10.1038/s41420-025-02577-8","DOIUrl":"10.1038/s41420-025-02577-8","url":null,"abstract":"<p><p>Colorectal cancer (CRC) treatment is still a challenge due to chemoresistance. We explored MEF2A function and underlying mechanism on cetuximab sensitivity in CRC. In this study, cancer tissues and adjacent non-cancerous samples were harvested from CRC patients. Cell viability, proliferation and apoptosis in CRC cells were tested by CCK-8, EdU, colony formation, and flow cytometry assays. The binding of MEF2A on the PD-L1 promoter was validated using luciferase reporter assay, CHIP, and EMSA, while the relationship of PD-L1 and SOX12 mRNA, as well as RBM15/IGF2BP1 and MEF2A mRNA, was verified by RIP, RNA pull-down, or FISH combined with immunofluorescence. m6A modification level of MEF2A mRNA was assayed by MeRIP. The expressions of key genes and proteins, including MEF2A, PD-L1, SOX12, RBM15, IGF2BP1, apoptosis- and cell cycle-related proteins, were determined with RT-qPCR, western blot, or immunohistochemistry. In vivo function of MEF2A was validated by establishing a xenograft nude mice model. The results showed that MEF2A was increased in CRC cells and tissues, while it was higher in cetuximab-resistant CRC tissues. Silencing MEF2A improved the sensitivity of cetuximab in CRC cells and xenograft mice. MEF2A binds to PD-L1 promoter to transcriptionally upregulate PD-L1 expression. Increased cetuximab sensitivity was observed in PD-L1 knockout (KO) CRC cells. PD-L1 overexpression reversed the enhanced cetuximab sensitivity induced by MEF2A knockdown. PD-L1 binds to SOX12 mRNA to stabilize its expression. PD-L1 knockdown augmented cetuximab sensitivity, which was overturned by SOX12 overexpression. The m6A modification mediated by RBM15/IGF2BP1 upregulated MEF2A expression in cetuximab-resistant CRC tissues. In conclusion, m6A-modified MEF2A alleviated cetuximab sensitivity in CRC via PD-L1/SOX12 mRNA axis, indicating that MEF2A might function as a promising therapeutic target against cetuximab-resistant CRC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"294"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539132","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":"Interplay between genes and social environment: from epigenetics to precision medicine.","authors":"Sabrina Caporali, Simone Russo, Marcel Leist, Petra H Wirtz, Ivano Amelio","doi":"10.1038/s41420-025-02580-z","DOIUrl":"10.1038/s41420-025-02580-z","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"293"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539127","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":"Making sense of human colorectal cancer molecular subtypes: mice are stepping in.","authors":"Caleb Green, Pamela Roccia, Alessandro Rufini","doi":"10.1038/s41420-025-02594-7","DOIUrl":"10.1038/s41420-025-02594-7","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"295"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12216249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539128","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":"Tumor metabolome remolded by low dose mitochondrial uncoupler elicites robust CD8⁺ T cell response.","authors":"Xiaoxiao Jiang, Zhijin Fan, Zhenzhen Zhang, Fanchu Zeng, Tong Sun, Yuchen Li, Guojia Huang, Liming Nie","doi":"10.1038/s41420-025-02584-9","DOIUrl":"10.1038/s41420-025-02584-9","url":null,"abstract":"<p><p>Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"291"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12215621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539136","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":"Modulatory role of radioprotective 105 in mitigating oxidative stress and ferroptosis via the HO-1/SLC7A11/GPX4 axis in sepsis-mediated renal injury.","authors":"Hong Duo, Yanwei Yang, Jun Luo, Yumeng Cao, Qian Liu, Jiarui Zhang, Siqi Du, Jian You, Guqing Zhang, Qifa Ye, Huaqin Pan","doi":"10.1038/s41420-025-02578-7","DOIUrl":"10.1038/s41420-025-02578-7","url":null,"abstract":"<p><p>Sepsis-associated acute kidney injury (SA-AKI) is a critical condition characterized by high morbidity and mortality rates, particularly in intensive care settings. This study focuses on RP105, a pattern recognition receptor, exploring its role in moderating the mechanisms of oxidative stress and ferroptosis during SA-AKI, offering insights into its potential as a therapeutic target. SA-AKI model was established using RP105 knockout (KO) and wild-type (WT) mice through cecal ligation and puncture (CLP). Comprehensive evaluations included the assessment of ferroptosis markers and the expression levels of pro-inflammatory cytokines. RP105 expression was markedly reduced in the kidneys following CLP induction, correlating with worsened renal outcomes. Compared to the Sham group, RP105^-/- mice displayed heightened renal damage, increased levels of oxidative stress markers, and enhanced lipid peroxidation. Notably, the deficiency of RP105 led to increased macrophage infiltration and a shift towards pro-inflammatory phenotypes, which further potentiated ferroptosis and exacerbated renal tissue damage. By influencing macrophage behavior and mitigating inflammatory responses. RP105 deficiency exacerbates macrophage-induced inflammation, oxidative stress, and ferroptosis, forming a vicious cycle that leads to more severe renal injury. These findings underscore the pivotal role of RP105 in mitigating oxidative stress and suppressing ferroptosis in the context of SA-AKI through regulation of the HO-1/SLC7A11/GPX4 axis. By preventing macrophage polarization toward a pro-inflammatory phenotype, RP105 alleviates inflammatory responses and tissue damage, highlighting its potential as a therapeutic target. Thus, RP105 emerges as a promising therapeutic candidate for mitigating sepsis-induced renal damage.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"290"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539130","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":"Circular RNA circLIMK1-005 promotes the progression of lung adenocarcinoma by interacting with RPA1 protein to activate CDK4 signaling.","authors":"Xia Yang, Lu Liu, Zhongjian Yu, Yuanlin Chen, Shiting Xu, Meiyuan Liu, Meng Wang, Huili Guo, Zhiwu Zhang, Bingjie Shan, Silin Cai, Mengting Pan, Jiangyu Zhang, Fengpin Wang, Yanfang Zheng","doi":"10.1038/s41420-025-02565-y","DOIUrl":"10.1038/s41420-025-02565-y","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide. Circular RNAs (circRNAs) have emerged as potential key players in the onset and progression of various cancers. However, the specific roles and mechanisms of circRNAs in LUAD remain largely unexplored. Here, we aimed to elucidate the role of a particular novel circRNA, circLIMK1-005 (hsa_circ_0002690), in the pathogenesis of LUAD. Our study revealed that circLIMK1-005 was upregulated in LUAD and correlated with poor patient prognosis. Functionally, circLIMK1-005 significantly promoted LUAD cell proliferation and metastasis. Mechanistically, circLIMK1-005 elevated the expression of Cyclin D1 and CDK4 proteins, thereby activating CDK4 signaling. We further demonstrated that circLIMK1-005 promoted LUAD progression by binding with RPA1 protein and activating the CDK4 pathway. In vivo experiments corroborated these findings, confirming that the circLIMK1-005/RPA1/CDK4 axis contributed to LUAD progression and was associated with poor clinical outcomes. Our study revealed a novel mechanism of the circLIMK1-005/RPA1/CDK4 axis in LUAD progression, and highlighted that targeting circLIMK1-005 could represent a potential therapeutic strategy for patients with LUAD. Schematic diagram of hypothesis involved in the circLIMK1-005/RPA1/CDK4 axis in LUAD progression. Figure was created with BioGDP.com.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"297"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539126","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":"Mutant p53 induces SH3BGRL expression to promote cell engulfment.","authors":"Lobsang Dolma, Mary I Patterson, Antonia Banyard, Callum Hall, Steven Bell, Wolfgang Breitwieser, Sudhakar Sahoo, John Weightman, Maria Pazos Gil, Garry Ashton, Caron Behan, Nicola Fullard, Lewis D Williams, Patricia Aj Muller","doi":"10.1038/s41420-025-02582-x","DOIUrl":"10.1038/s41420-025-02582-x","url":null,"abstract":"<p><p>Previously, we identified that mutant p53 expression in cancer cells promotes engulfment of neighbouring cancer cells to form cell-in-cell (CIC) structures. This process gave mutant p53 cells an advantage in tumour formation in mouse xenograft experiments. TP53 can be found mutated at nearly every amino acid in cancers and mutant p53 expression is associated with various GOF (Gain-of-function) processes, including cancer cell invasion, metastasis, stemness and drug resistance. In the current manuscript, we identified SH3BGRL (Src homology 3 binding glutamate rich protein like) as a mutant p53-regulated gene and investigated to what extent SH3BGRL expression and cell engulfment are responsible for mutant p53-dependent anchorage-independent growth and chemoresistance. We demonstrate that mutant p53 expression drives cell engulfment in which the mutant p53 host cell moves in the direction of the target internal cell to form CIC structures. This is therefore more reminiscent of cell engulfment rather than cell entosis, in which cells invade into host cells. Using NGS (Next Generation Sequencing), we identified novel target genes of mutant p53 and demonstrate that cell engulfment requires SH3BGRL expression. We generated mutant p53 and p53 KO cell lines that stably overexpressed SH3BGRL and determined that SH3BGRL promotes etoposide resistance in mutant p53 cells and anchorage-independent growth independent of mutant p53 expression. Through FACS sorting of pure cell engulfing (CIC) populations, we could also show that engulfing cells have an enhanced etoposide resistance. These data suggest that SH3BGRL and cell engulfment are required for certain GOFs of mutant p53.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"288"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539131","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":"The biogenesis and biological roles of migrasomes in human diseases.","authors":"Yifan Zhang, Wei Chen, Jiageng Zhu, Luwei Xu","doi":"10.1038/s41420-025-02569-8","DOIUrl":"10.1038/s41420-025-02569-8","url":null,"abstract":"<p><p>Migrasomes are recently identified extracellular vesicles that are specifically generated by migrating cells. These pomegranate-like, membrane-bound organelles are released at the trailing edge during cell migration and play crucial roles in cell-to-cell communication, intercellular signaling, and tissue remodeling. Migrasomes selectively package various molecular components, including proteins, lipids, and RNA, facilitating a unique form of cellular communication known as migracytosis. They are involved in numerous physiological and pathological processes, including immune responses, cancer metastasis, tissue repair, and embryonic development. In this review, we provide an in-depth analysis of the biogenesis, structural features, and molecular composition of migrasomes. We further explore the emerging roles of migrasomes in disease pathogenesis, particularly their potential in cancer, neurodegenerative diseases, and immune modulation. Overall, this review aims to offer comprehensive insights into the latest research on migrasomes, while addressing the challenges in their study and potential avenues for future clinical implementation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"296"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539135","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":"RCOR1 promotes myoblast differentiation and muscle regeneration.","authors":"Martina Pauk, Fan Wang, Petri Rummukainen, H G Mauricio Ramm, Hanna Taipaleenmäki, Riku Kiviranta","doi":"10.1038/s41420-025-02568-9","DOIUrl":"10.1038/s41420-025-02568-9","url":null,"abstract":"<p><p>RCOR proteins belong to a family of highly conserved transcription corepressors (RCOR1, RCOR2 and RCOR3) that regulate the activity of associated histone demethylase 1 (LSD1) and histone deacetylase 1/2 (HDAC 1/2) in chromatin-modifying complexes. Despite the described function of LSD1 in skeletal muscle differentiation and regeneration, the role of RCOR family in myogenesis remains unknown. We found that RCOR1 is highly expressed in proliferating myoblasts and activated satellite cells, but not in mature myofibers during postnatal skeletal muscle growth and regeneration. Silencing of RCOR1 impaired myoblast differentiation and fusion, as evidenced by reduced levels of myogenin and MyHC, key markers of myogenic commitment. Moreover, RCOR1 depletion impaired myoblast proliferation through upregulation of the cell cycle inhibitor P21. Although combined silencing of P21 and RCOR1 rescued the proliferation defect of RCOR1 deficiency alone, it failed to restore differentiation, suggesting that RCOR1 action on myoblast proliferation and differentiation is mediated via independent mechanisms. RCOR1 was found physically associated with LSD1 and myogenic regulatory factor MyoD and contributed to LSD1 stability in myoblasts via ubiquitination. Accordingly, the repressive effect of RCOR1 depletion on myogenic differentiation was rescued by LSD1 overexpression, indicating that RCOR1 exerts its function on myoblast differentiation primarily through LSD1. Consistently, in a mouse model of skeletal muscle injury, depletion of RCOR1, accompanied with reduction of LSD1, supressed satellite cell activation and differentiation which resulted in impaired muscle regeneration. Together, our findings indicate that RCOR1 acts in concert with LSD1 as a novel positive regulator of myogenesis and skeletal muscle regeneration.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"298"},"PeriodicalIF":6.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539134","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":"Development of translational read-through-inducing drugs as novel therapeutic options for patients with Fanconi anemia.","authors":"Anca Manuela Hristodor, Enrico Cappelli, Elena Baldisseri, Roberto Valli, Giuseppe Montalbano, Giovanni Micheloni, Giovanni Porta, Annalisa Frattini, Silvia Ravera, Francesca Fioredda, Giuseppe Lippi, Carlo Dufour, Marco Cipolli, Valentino Bezzerri","doi":"10.1038/s41420-025-02571-0","DOIUrl":"10.1038/s41420-025-02571-0","url":null,"abstract":"<p><p>Fanconi anemia (FA) is caused by mutations affecting FANC genes involved in DNA repair, with nearly 20% of FA patients harboring nonsense mutations. Ataluren (PTC124) is a translational read-through-inducing drug (TRID) already approved in Europe that has a well-established safety profile even in pediatric patients. Amlexanox, an anti-inflammatory drug, also promotes read-through of premature stop codons caused by nonsense mutations. We compared ataluren and amlexanox in rescuing FANCA, FANCC and FANCF protein synthesis in lymphoblastoid cell lines and fibroblasts obtained from FA patients with nonsense mutations. While ataluren restored all FANC protein levels, amlexanox was partially effective only on FANCA. Notably, the rescue of FANC proteins resulted in a significant downregulation of p53. Moreover, unlike amlexanox, ataluren remarkably improved cell viability and reduced chromosomal aberrations upon exposure to genotoxic compounds. Amlexanox primarily reduced the signal transducer and activator of transcription 2 (STAT2) phosphorylation. Furthermore, FANCA-mutated fibroblasts exhibited a higher frequency of micronuclei formation as well as lower lamin B1 expression compared to their gene-edited counterpart re-expressing wild-type FANCA. Interestingly, ataluren significantly limited the generation of micronuclei in nonsense-mutated primary FANCC fibroblasts, restoring lamin B1 expression. This study represents a milestone of drug development for FA as it paves the way for clinical development of TRIDs, indicating ataluren as a promising approach to address the genetic instability and reduce the risk of malignant transformation in FA cells. Moreover, these results highlight the importance of a reliable experimental pipeline to assess whether minimal protein rescue via translational read-through can yield meaningful phenotypic rescue.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"286"},"PeriodicalIF":6.1,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339938","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}