Cell Death Discovery最新文献

{"title":"CRISPR-Cas9 screening reveals G2E3 as a novel ubiquitin-linked factor controlling autophagosome-lysosome fusion and cancer cell progression.","authors":"Yumei Gong, Marc Leon, Huaqing Mo, Premkamol Pengpaeng, Hai Yang, Yanxi Lu, Zhiqiang Yin, Alan Benard, Yong Zhou, Robert Grützmann, Christian Pilarsky","doi":"10.1038/s41420-025-02717-0","DOIUrl":"https://doi.org/10.1038/s41420-025-02717-0","url":null,"abstract":"<p><p>Autophagy is a tightly regulated process essential for cellular homeostasis, with ubiquitination playing a crucial role in its regulation. However, the specific ubiquitin related factors involved in autophagic flux remain largely unexplored. Identifying these regulators is essential for advancing the mechanistic understanding of autophagy and its broader implications in cellular function. This study aimed to identify novel ubiquitination-associated regulators of autophagy. To achieve this, we conducted a CRISPR-Cas9 loss-of-function screen targeting 660 ubiquitination-related genes in pancreatic cancer cells expressing the mCherry-GFP-LC3 autophagy flux reporter system. Among the top candidates, we identified G2E3, a G2/M-phase-specific E3 ubiquitin ligase, as a previously unrecognized autophagy regulator. Subsequent functional analyses revealed that G2E3 knock out led to a significant accumulation of LC3B-II and GABARAPs, indicative of impaired autophagic flux. Further confocal imaging demonstrated that the co-localization of LC3B with LAMP1-positive lysosomes was significantly reduced in G2E3 knock out cells, suggesting defective autophagosome-lysosome fusion. Mechanistically, G2E3 directly interacts with GABARAP and GABARAPL1, but not LC3B, positioning it as a key regulator of late-stage autophagy. Additionally, G2E3 knock out cells exhibited reduction in migration and invasion capability, suggesting its role in cancer progression. These findings establish G2E3 as a novel ubiquitin-related regulator of autophagy, specifically facilitating autophagosome-lysosome fusion via a GABARAPs-dependent mechanism. This study reveals a previously unrecognized role of G2E3 in late-stage autophagy and suggests that targeting G2E3 could provide a potential therapeutic approach for modulating autophagy-dependent cellular processes, including cancer progression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"455"},"PeriodicalIF":7.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC25A10 promotes cisplatin resistance by inhibiting ferroptosis in cervical cancer.","authors":"Chenglei Ma, Xiaoyi Lu, Chen Ni, Yu Gao, Fei Yang, Shiwen Chen, Yi Du, Fang Zhao, Ying Cao, Haiwei Huang","doi":"10.1038/s41420-025-02712-5","DOIUrl":"10.1038/s41420-025-02712-5","url":null,"abstract":"<p><p>Cisplatin (DDP)-based chemotherapy is the standard first-line treatment for cervical cancer (CC). However, many patients with CC develop resistance to DDP, either initially or over time. This resistance significantly limits the effectiveness of treatment. Therefore, identifying new therapeutic targets and combination therapies to overcome DDP resistance is a critical need. In this study, we investigated the expression of SLC25A10 in cervical cancer tissues using bioinformatics analysis and partial tissue analysis. We found that SLC25A10 expression was significantly higher in human cervical cancer tissues compared to normal tissues, based on data from The Cancer Genome Atlas (TCGA) and clinical samples. Moreover, increased SLC25A10 expression was associated with adverse clinicopathological characteristics of cervical cancer patients. To explore the functional role of SLC25A10, we conducted a series of in vitro and in vivo experiments. Our results demonstrated that SLC25A10 promotes cervical cancer cell growth, migration, and resistance to DDP. Mechanistically, we found that inhibiting SLC25A10 expression restricted the transport of glutathione (GSH) and reduced the expression of glutathione peroxidase 4 (GPX4). This led to increased intracellular lipid peroxidation and accumulation of reactive oxygen species (ROS), ultimately promoting iron-mediated cell death (ferroptosis) in cervical cancer cells. In conclusion, our findings suggest that SLC25A10 may serve as a novel therapeutic target to overcome cisplatin resistance and enhance the efficacy of chemotherapy in CC. Future studies should focus on further elucidating the role of SLC25A10 in CC and exploring its potential as a therapeutic target in combination with other treatments.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"447"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243861","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":"Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance.","authors":"Shilpi Singh, Iteeshree Mohapatra, Debashis Barik, Haoyi Zheng, Stefan Kim, Mayur Sharma, Clark C Chen, Gatikrushna Singh","doi":"10.1038/s41420-025-02744-x","DOIUrl":"10.1038/s41420-025-02744-x","url":null,"abstract":"<p><p>Glioblastoma remains the most aggressive and treatment-resistant brain malignancy, driven by genetic heterogeneity, metabolic plasticity, and an immunosuppressive tumor microenvironment (TME). Current therapies rely on inducing tumor cell death through DNA damage; however, glioma stem cells (GSCs) upregulate compensatory DNA repair pathways, promoting resistance and tumor recurrence. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, offers a novel therapeutic strategy to overcome therapy resistance by exploiting glioblastoma's metabolic vulnerabilities. Unlike conventional therapies, ferroptosis bypasses DNA repair mechanisms, making it particularly effective against therapy-resistant GSCs. It reduces tumor growth by triggering iron-catalyzed oxidative stress, disrupting lipid metabolism, and pushing glioblastoma cells beyond their oxidative threshold. However, resistance mechanisms to ferroptosis, including iron metabolism regulators (IREB2 and ferritinophagy), lipid peroxidation enzymes (ACSL4 and ALOXs), and protective pathways (cystine transporters and glutathione peroxidase 4), limit its therapeutic potential. Extracellular vesicle-mediated iron transfer further contributes to ferroptosis resistance, fostering chemoresistance and radio-resistance. Beyond direct tumor killing, ferroptosis modulates the TME by releasing damage-associated molecular patterns, inducing reactive oxygen species, stimulating CD8⁺ T-cell activation, enhancing immune checkpoint blockade efficacy, and reprogramming tumor-associated macrophages toward an anti-tumor phenotype. Ferroptosis-based strategies, including glutathione peroxidase 4 inhibitors, nanoparticle-mediated iron delivery, and RNA-based therapies, offer promising avenues for enhancing glioblastoma treatment efficacy. This review highlights ferroptosis as a promising strategy for overcoming glioblastoma resistance by integrating it with chemotherapy, radiotherapy, and immunotherapy to enhance treatment efficacy. Given the complexity of glioblastoma, personalized ferroptosis-based approaches that address tumor heterogeneity, immune interactions, and metabolic adaptations are crucial for overcoming therapy resistance. Refining ferroptosis-targeted strategies by incorporating metabolic, immune, and genetic considerations can lead to more durable and effective therapies, ultimately transforming glioblastoma treatment and improving patient outcomes.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"448"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243899","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":"MiR-140-3p regulates axonal motor protein KIF5A and contributes to axonal transport degeneration in SMA.","authors":"Markella Baklou, Valeria Valsecchi, Giusy Laudati, Xhesika Kolici, Paola Brancaccio, Nunzia De Iesu, Serenella Anzilotti, Federica Cieri, Giuseppe Pignataro","doi":"10.1038/s41420-025-02663-x","DOIUrl":"10.1038/s41420-025-02663-x","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a paediatric neuromuscular disease caused by alterations of the survival motor neuron (SMN) gene, which results in progressive degeneration of motor neurons (MNs). Although effective treatments for SMA patients has been recently developed, the molecular pathway involved in selective MNs degeneration has not been yet elucidated. Disruption of axonal transport is a common feature of motor neuron diseases (MNDs); specifically, mutations at the C-terminal of the kinesin KIF5A, have been linked to neurodegenerative disorders involving MNs degeneration such as amyotrophic lateral sclerosis (ALS). Therefore, the present study attempts to investigate potential alterations of the axonal transport complex that includes KIF5A in a SMA mouse model. We demonstrated that KIF5A is downregulated in the spinal cord of SMA mice both in early and late phases of the disease. A miRNA-based strategy was developed in the attempt to prevent KIF5A downregulation, thus restoring its physiological levels. Indeed, we demonstrated that miR-140-3p was up-regulated in the spinal cord of SMA mice during disease progression and was able to negatively modulate KIF5A expression. Furthermore, the intracerebroventricular injection of an antagomir molecule, able to block miR140-3p function, resulted in a reduction of SMA severity in terms of improved behavioural performance. Based on these results, we indicated KIF5A as a distinctive mechanism of MNDs progression and suggested that developing a strategy able to prevent KIF5A downregulation could be beneficial, not only in SMA but also in other neurodegenerative diseases.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"446"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243876","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":"Insufficient NNMT promotes autophagy and disrupts progesterone signaling in endometrial stromal cells in recurrent implantation failure by modulating the H3K9me3-ALDH1A3 pathway.","authors":"Yifei Song, Shaotong Zhao, Xianping Hou, Jiayuan Chen, Qian Zhang, Shizhen Su, Junhao Yan, Tianxiang Ni","doi":"10.1038/s41420-025-02752-x","DOIUrl":"10.1038/s41420-025-02752-x","url":null,"abstract":"<p><p>Defective endometrial receptivity represents an important factor in recurrent implantation failure (RIF), though its precise regulatory mechanisms remain unclear. While nicotinamide N-methyltransferase (NNMT) is abundantly expressed in human endometrial tissues, its role in endometrial receptivity and RIF pathogenesis has not been defined. This study demonstrated that NNMT expression was significantly downregulated in midluteal-phase endometrium from RIF patients relative to fertile controls. Functional analyses in human endometrial stromal cells (ESCs) revealed that NNMT knockdown enhanced autophagy flux and disrupted progesterone signaling. Mechanistically, NNMT deficiency elevated H3K9me3 enrichment at the Aldh1a3 promoter, suppressing its expression. Notably, knockdown of ALDH1A3 resulted in similar effects with NNMT downregulation, and exogenous rhALDH1A3 reversed the autophagy alterations and rescued progesterone signaling in NNMT-knockdown cells. In vivo, NNMT inhibition in a murine model reduced embryo implantation rates and decreased ALDH1A3 expression. Collectively, these findings indicate that reduced NNMT impairs endometrial receptivity through H3K9me3-mediated ALDH1A3 repression, leading to aberrant autophagy and disrupted progesterone signaling in decidualized ESCs. This study identifies the NNMT-H3K9me3-ALDH1A3 axis as a key epigenetic-metabolic pathway underlying RIF, offering novel diagnostic and therapeutic targets.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"450"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243890","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":"KDM4B modulates ERα signaling pathway to participate in vascular smooth muscle cell calcification.","authors":"Fei Liu, Yang Lv, Yanxia Lin, Chunyu Wang, Shengli Wang, Kai Zeng, Baosheng Zhou, Lin Lin, Jianwei Feng, Ge Sun, Xiaocen Chang, Mengsu Cao, Hao Li, Xihong Hu, Shigeaki Kato, Yue Zhao, Wen Tian","doi":"10.1038/s41420-025-02765-6","DOIUrl":"10.1038/s41420-025-02765-6","url":null,"abstract":"<p><p>Vascular calcification (VC) is recognized as an independent predictor of cardiovascular events. Although estrogen replacement is a controversial treatment due to its potential carcinogenic effects, it was considered a protective treatment against VC in postmenopausal women. Estrogen receptor α (ERα) co-regulators were considered as potential therapeutic targets for ERα-related cancers. However, ERα activity and the biological function modulation of ERα co-regulators in VC remain elusive. Histone lysine demethylase 4B (KDM4B) was identified to be highly expressed in human and mouse aortic smooth muscle (ASMC) cells treated with β-phosphoglycerol and in mice overloaded with VitD3 during calcification, as evidenced by western blotting and immunofluorescence staining. Co-immunoprecipitation (Co-IP) was performed to show the association between KDM4B and ERα. Our data demonstrated that KDM4B down-regulated ERα-induced transactivation and that KDM4B depletion increased mRNA expression of endogenous ERα target genes. Furthermore, we provided the evidence to show that KDM4B is associated with Polycomb repressive complex 2 (PRC2) and ERα. In addition, KDM4B depletion decreased the recruitment of PRC2 complex to estrogen response element (ERE) regions of ERα target gene, thereby down-regulating the H3K27me3 levels. Finally, KDM4B-mediated enhancement of ASMCs' calcification was partially attenuated by the estrogen treatment. KDM4B inhibits ERα-induced transactivation independent of its Jumanji-C enzyme active region. Taken together, our study suggests that KDM4B acting as ERα co-repressor is involved in the regulation of VC, indicating that KDM4B may be a new potential therapeutic target for VC treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"452"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243930","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 effect of TIM1⁺ Breg cells in myocardial ischemia-reperfusion injury.","authors":"Cong Zeng, Jianchuan Qi, Feifei Wu, Weijun Yang, Minjian Kong, Haifeng Cheng, Aiqiang Dong, Jie Han, Wei Chen, Dajin Chen, Qunjun Duan","doi":"10.1038/s41420-025-02725-0","DOIUrl":"10.1038/s41420-025-02725-0","url":null,"abstract":"<p><p>Recent studies found that treatment with an anti-T-cell immunoglobulin mucin-1 (TIM1) monoclonal antibody (RMT1-10) regulated immune responses by inducing regulatory B cells (Bregs). However, the role of these cells in myocardial ischemia-reperfusion injury (IRI) is unknown. This study aimed to investigate the protective effect of RMT1-10 on myocardial IRI and its potential mechanism. We established a myocardial IRI model, and Triphenyl tetrazolium chloride staining, Terminal deoxynucleotidyl transferase nick-end-labeling, hematoxylin and eosin, and transmission electron microscopy were performed to examine the myocardial infarction size, myocardial cell apoptosis, and cardiomyocyte morphology and structure. The data showed that RMT1-10 could alleviate myocardial IRI, increase the number of TIM1⁺Bregs and interleukin 10 (IL-10) secretion, and regulate the expression of inflammatory factors after myocardial IRI. However, treatment with RMT1-10 and Anti-CD20 abrogated the protective effect of RMT-10. In addition, RMT1-10 treatment inhibited T cells but significantly activated Tregs after IRI, while RMT1-10 combined with Anti-CD20 abolished this effect on Tregs. Furthermore, sequencing analysis showed marked expression changes among genes related to several classical signaling pathways in response to RMT1-10. Taken together, these findings indicated that RMT1-10 could increase the number of TIM1⁺ Bregs and regulate IL-10-mediated inflammatory reactions, activate Tregs to inhibit inflammation, and might regulate the above-mentioned signaling pathways to protect against myocardial IRI.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"453"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243884","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":"Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress.","authors":"Yi-Fang Yang, Zhao-Jing He, Han-Hsi Kuo, Yu-Yu Lin, Cheorl-Ho Kim, Huei-Yu Cai, Chi-Long Chen, Michael Hsiao, Ying-Chung Chen, Peter Mu-Hsin Chang, Yu-Chan Chang","doi":"10.1038/s41420-025-02755-8","DOIUrl":"10.1038/s41420-025-02755-8","url":null,"abstract":"<p><p>Estrogen receptor-positive (ER⁺) breast cancer is commonly treated with hormone therapy; however, these tumors frequently develop drug resistance and exhibit poor responses to radiotherapy. To investigate the molecular basis of therapy resistance, we explored the role of estrogen receptor alpha (ESR1) in modulating sensitivity to oxidative and radiation stress. Through integrative analysis of publicly available datasets, we identified ESR1 as a key molecular marker associated not only with breast cancer classification but also with radiosensitivity. In ER⁺ breast cancer cell lines, higher endogenous ESR1 expression correlated with increased resistance to ionizing radiation. Functional studies using ESR1 overexpression and knockdown models revealed that depletion of ESR1 sensitized cells to radiation-induced DNA damage, impaired DNA repair efficiency, and reduced clonogenic survival. Notably, we found that the ESR1-SQSTM1 (p62) interaction impairs autophagic flux, contributing to treatment resistance. Mechanistically, ESR1 translocates to the cytoplasm and binds to SQSTM1, thereby disrupting autophagosome maturation. Furthermore, estradiol enhances ESR1 phosphorylation and its affinity for SQSTM1, reinforcing this inhibitory effect on autophagy and promoting resistance to radiation. Our findings uncover a previously unrecognized ESR1-SQSTM1 axis that governs autophagy and redox response in ER⁺ breast cancer. Targeting this pathway may restore sensitivity to radiotherapy and offer a new therapeutic strategy. Assessment of ESR1 expression and autophagy activity may serve as predictive biomarkers for treatment response in ER⁺ breast cancer patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"451"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243920","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 RNAs and mammalian follicular development: current insights and future prospects-an updated review.","authors":"Huifeng Li, Tianle He, Dengjun Ma, Huanhuan Gong, Zhenguo Yang","doi":"10.1038/s41420-025-02661-z","DOIUrl":"10.1038/s41420-025-02661-z","url":null,"abstract":"<p><p>Circular RNAs (circRNAs), a newly recognized category of non-coding RNA, have recently become a central point of interest in biological research. The ovaries are critical reproductive organs in female mammals, profoundly influencing fertility through their effects on endocrine functions and follicular cycle activities. Follicle development, as the fundamental functional component of the ovaries, is elaborately regulated by granulosa cells, oocytes, and endocrine signals. Recent research has progressively underscored the critical role of circRNAs in regulating follicular development and maturation in mammalian species. This review comprehensively examines the formation, molecular characteristics, and biological significance of circRNAs during mammalian follicular development, with a specific focus on their regulatory mechanisms and functional patterns in this process. We propose that future research should continue to explore the specific mechanisms by which circRNAs influence follicular development in mammals, including their interactions with other non-coding RNAs, the mechanisms of their interaction with the follicular microenvironment, and the alterations in follicular environments under pathological conditions, including polycystic ovary syndrome (PCOS) and primary ovarian insufficiency (POI). Furthermore, we analyze the potential contributions of circRNAs in follicular development in view of advances in high-throughput sequencing technologies and gene editing tools, aiming to deepen our understanding of the biological significance of circRNAs in this context. In summary, this review elucidates the specific mechanisms and critical roles of circRNAs in follicular development in female mammals, potentially providing new therapeutic targets and strategies for future reproductive medicine and fertility treatments.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"454"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243922","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":"Aging aggravated liver ischemia and reperfusion injury by promoting oxidized mtDNA mediated-macrophage pyroptosis through acetylated MCU-dependent calcium uptake.","authors":"Xin-Yi Wu, Rui Wang, Qi Zhang, Tao Liu, Jun-Yan Liu, Xue-Song Xu, Jun-Hua Gong","doi":"10.1038/s41420-025-02746-9","DOIUrl":"10.1038/s41420-025-02746-9","url":null,"abstract":"<p><p>The shortage of liver donors for liver transplantation is currently an urgent problem. Elderly donors have become an important source of donor livers, but they are more prone to ischemia reperfusion injury (IRI) in liver transplantation. Therefore, exploring the effects and mechanisms of aging on liver IRI will provide a new theoretical basis for improving the survival rate of liver transplant patients. We constructed a mouse model of liver ischemia for 90 min and reperfusion for 6 or 24 h, and found that compared with young liver, the recovery of liver function in aged liver after IRI was slower. Detection of macrophage pyroptosis revealed that it was an important factor for aging deferring liver function restoration. Mechanistically, we demonstrated that aging triggered mitochondrial permeability transition pore (mPTP) channel opening to promote the release of Oxidized mtDNA (Ox-mtDNA), thereby inducing macrophage pyroptosis. Moreover, the activity of mPTP channel was mainly dependent on calcium uptake by acetylated mitochondrial calcium uniporter (MCU). These results illustrated that cytoplasmic Ox-mtDNA-induced macrophage pyroptosis was a key factor for aging exacerbating liver IRI. Calcium uptake via acetylated MCU triggered mPTP channel opening, which is an important mechanism for Ox-mtDNA release from mitochondria into the cytoplasm.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"449"},"PeriodicalIF":7.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243913","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}