Cell Death & Disease最新文献

{"title":"Comprehensive characterisation of age-related changes in cell subpopulations and tissue structural properties in secondary lymphoid organs.","authors":"Yuxin Deng, Xin He, Juzheng Peng, Yuxi Pan, Yusheng Luo, Yueheng Ruan, Jianfeng Hou, Bangxue Jiang, Xiangyu Li, Xiaomei Liang, Jiayuan Huang, Jiancheng Wang","doi":"10.1038/s41419-025-08007-y","DOIUrl":"10.1038/s41419-025-08007-y","url":null,"abstract":"<p><p>Population aging is an escalating global phenomenon, wherein age-related alterations in the human immune system exacerbate the susceptibility to diseases including infections and autoimmune disorders. Secondary lymphoid organs (SLOs) are key locations for the execution of immunological responses by mature immune cells; however, age-related changes in SLOs remain relatively understudied. To address this gap, this study employed comprehensive approaches including single-cell RNA sequencing (scRNA-seq) data analysis, immunofluorescence staining, flow cytometry, and morphological analysis, to clarify the age-related alterations in SLOs in mice. The results demonstrated that aging caused senescent immune cells to accumulate and subpopulations to reorganize, with a decrease in the proportion of naïve T cells, whilst an increase in regulatory T (Treg) cells, cytotoxic T lymphocytes (CTLs), and exhausted T (Tex) cells. Notably, CD4⁺ and CD8⁺ T cells exhibited distinct senescence patterns in Peyer's patches, suggesting tissue-specific responses to aging, which may arise from differential exposure to gut microbiota. In addition to the alterations in immune cell populations, we also identified increased stromal cell senescence and altered distributions of marginal reticular cells and follicular dendritic cells, which may further contribute to age-related immune dysfunction. Finally, examining SLO structural features, including size, fibrosis, stiffness, and pigmentation, revealed degenerative changes that impair immune function. Collectively, this study will assist with the development of strategies aimed at delaying aging and treating age-related diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"679"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.","authors":"Aravindan Narayanan, Souvik Guha, Avinash Mali, Sharmila A Bapat","doi":"10.1038/s41419-025-07987-1","DOIUrl":"10.1038/s41419-025-07987-1","url":null,"abstract":"<p><p>Ex vivo stem cell self-renewal and maintenance is supported by absence of serum-derived mitogens. In the present study, we sought to elucidate the proteomes of stem-like cells grown in serum-free media across a panel of high-grade serous ovarian cancer cell lines, which encompass a gradient from epithelial, intermediate and mesenchymal cell phenotypes to recapitulate the heterogeneity of the disease. MaxQuant-based label-free quantification of proteins identified that despite their different cellular and molecular architectures, all phenotypes exhibited mitochondria- and stemness-related pathways under conditions of serum starvation, although the specific proteins involved were discrete to each phenotype. This suggests that common cellular programs in a disease can be mediated through variable biological networks that generates molecular heterogeneity. We further explored if these pathways are inter-related, co-regulated or just incidentally associated in response to an environment depleted of growth factors and mitogens. Irrespective of their phenotype, cell lines on serum-starvation displayed an increased amount of mitochondrial DNA, mitochondrial biogenesis and mitochondrial activity with a switch from glycolysis to oxidative phosphorylation fuelled by the fatty acid oxidation. Ultra-structural studies implicated this metabolic fluctuation was regulated by dynamic mitochondrial remodelling. This also led us to explore a possible therapeutic strategy of targeting mitochondrial function to restrict tumor regenerative potential and disease recurrence. Conclusively, these new avenues contribute to a more comprehensive understanding of ovarian cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"676"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The deubiquitylase OTUB1 drives gemcitabine resistance in pancreatic cancer by enhancing pyrimidine metabolism through modulating DHODH mRNA stability.","authors":"Wenming Zhang, Rui Liu, Junwen Hu, Shuangyan Wan, Yeqin Zou, Tong Che, Jin Zhang, Leifeng Chen, Xiaogang Peng","doi":"10.1038/s41419-025-08001-4","DOIUrl":"10.1038/s41419-025-08001-4","url":null,"abstract":"<p><p>Gemcitabine resistance is a major clinical challenge in pancreatic cancer (PC); therefore, strategies to combat gemcitabine resistance are urgently required. Reprogramming pyrimidine metabolism by oncogenic signaling contributes to cancer progression and confers chemoresistance to many cancers. The current study identified the deubiquitinating enzyme OTUB1 as a promising therapeutic target for combating gemcitabine resistance in PC. OTUB1 was found to be aberrantly expressed in PC and remarkably correlated with poor patient survival. Both in vivo and in vitro, OTUB1 knockdown increased the gemcitabine efficacy of PC cells by inhibiting pyrimidine metabolism. Furthermore, OTUB1 enhanced de novo nucleotide pyrimidine synthesis in PC cells by upregulating dihydroorotate dehydrogenase (DHODH), a critical rate-limiting enzyme for pyrimidine de novo biosynthesis. Mechanistically, OTUB1 suppressed the degradation and polyubiquitination of the RNA-binding protein DEAD-box helicase 3 X-linked (DDX3X), which in turn stabilized DDX3X-mediated DHODH mRNA. OTUB1 interacts with DDX3X, and the binding stabilizes DDX3X through its deubiquitinase activity. In addition, a small-molecule OTUB1 inhibitor combined with gemcitabine treatment could synergistically inhibit tumor growth in high-OTUB1-expressing murine tumoroids. Collectively, OTUB1 could impart gemcitabine resistance by promoting de novo pyrimidine synthesis, and targeted suppression of OTUB1 could be an effective strategy to overcome gemcitabine resistance in PC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"697"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of RUNX2 promotes breast cancer multi-organ metastasis through stabilizing c-Myc.","authors":"Tian-Hao Zhou, Hao Fu, Shuai Zhao, Wen-Jing Jiang, Sen Miao, Hao Tan, Rui Zhang, Qing-Shan Wang, Yu-Mei Feng","doi":"10.1038/s41419-025-08018-9","DOIUrl":"10.1038/s41419-025-08018-9","url":null,"abstract":"<p><p>Distant metastasis is the leading cause of mortality in breast cancer patients and remains a significant challenge in clinical practice. Although breast cancer metastasis exhibits organotropism, widespread dissemination and synchronous multi-organ metastasis frequently occur in advanced stages, or the early stages of patients suffering from aggressive tumors, even in patients with an undetectable primary tumor. However, the underlying mechanism is still far from being fully understood. Runt-related transcription factor 2 (RUNX2), a master osteogenic transcription factor, is commonly considered a driver of bone-specific metastasis in breast cancer. Surprisingly, we found here that overexpression of RUNX2 drives synchronous multi-organ metastases rather than bone-preferred metastasis in multiple mouse models of breast cancer, regardless of subtype. Mechanistically, RUNX2 physically interacts with c-Myc oncoprotein to prevent FBXW7-mediated ubiquitination and degradation of c-Myc and coordinately activates the transcription and expression of c-Myc target genes, which elicit early progression and spontaneous dissemination from primary tumor mass, rapid engraftment, and unrestrained outgrowth of cancer cells in distant organs. Thus, our findings uncover a novel mechanism of multi-organ metastasis and highlight RUNX2‒c-Myc regulatory axis as a prognostic indicator and a therapeutic target for predicting and managing multi-organ metastatic breast cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"696"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and ¹²⁵I brachytherapy sensitization in esophageal carcinoma.","authors":"Xijuan Yao, Cheng Feng, Xing Huang, Songzhe Wu, Shuting Lu, Yang Gao, Tong Sun, Xiaxing Bai, Chenghui Li, Kaizhi Jia, Xue Han, Zhongkai Wang, Binda Chen, Xiaobin Wang, Jinhe Guo, Jian Lu","doi":"10.1038/s41419-025-07864-x","DOIUrl":"10.1038/s41419-025-07864-x","url":null,"abstract":"<p><p>Interventional brachytherapy, such as iodine-125(¹²⁵I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after ¹²⁵I brachytherapy. It is key to decipher the underlying mechanism of ¹²⁵I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to ¹²⁵I treatment. Mechanistically, P4HA2 enhances mitochondrial autophagy (mitophagy) via the PINK1/parkin pathway by binding to ATAD3A. Clinically, high expression of P4HA2 correlates with shorter overall survival and predicts poor prognosis with ¹²⁵I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m⁶A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to ¹²⁵I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated ¹²⁵I radioresistance, which provides a potential therapeutic target and combinatorial strategy. Schematic diagram of the role of P4HA2 in ¹²⁵I brachytherapy for tumors.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"685"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypermethylation-mediated HNF4A silencing by Helicobacter pylori infection drives gastric cancer by disrupting epithelial cell polarity and activating EMT signaling.","authors":"Dandan Li, Zeng Zhou, Xinqi Li, Qiwei Guo, Lin Yuan, Xiangang Zhang, Lantian Zhai, Lingyun Xia, Weidong Leng, Shanshan Qin","doi":"10.1038/s41419-025-08029-6","DOIUrl":"10.1038/s41419-025-08029-6","url":null,"abstract":"<p><p>Helicobacter pylori (Hp.) infection is one of the high-risk factors for gastric carcinogenesis (GC). However, the underlying mechanism remains largely unclear. In this study, we uncover an essential role of Hp. infection in mediating tumor suppressor gene silencing in gastric epithelial cells through promoter DNA hypermethylation. Hepatocyte nuclear factor HNF4A was downregulated in GC and predicted poor survival. The in vitro and in vivo assays together confirmed that HNF4A plays a tumor suppressive role in GC. Single-cell analysis showed that HNF4A was selectively expressed in gastric epithelial cells. Besides, the reduced HNF4A expression in GC was due to promoter DNA hypermethylation. More importantly, we have provided strong evidence that Hp. infection causes HNF4A down-regulation by hypermethylation of its gene promoter. Meanwhile, silencing of HNF4A resulted in loss of epithelial polarity and activation of TGFβ-induced EMT signaling in gastric epithelial cells by transcriptionally regulating the expression of downstream target genes. In addition, the rescue assays indicated that Hp. infection activated EMT signaling of gastric epithelial cells in a HNF4A-dependent manner, thereby driving gastric tumorigenesis and metastasis. In conclusion, HNF4A is a tumor suppressor gene in GC. Hp. infection causes silence of the HNF4A gene by hypermethylation of its promoter, which then disrupts epithelial polarity and induces EMT signaling in gastric epithelial cells, thereby driving gastric tumorigenesis and metastasis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"688"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose-tumor crosstalk in colorectal cancer: Identifying (Epi)genetic biomarkers for tumor progression and cachexia.","authors":"Ada Pesapane, Lucia Capasso, Maria Rosaria Del Sorbo, Lucia Scisciola, Teresa Troiani, Donato Mele, Martina Franzese, Armando Puocci, Giovanni Tortorella, Surina Surina, Giacomo Fuschillo, Francesco Caraglia, Vincenzo De Falco, Lucio Selvaggi, Rosaria Anna Fontanella, Fortunato Ciardiello, Francesco Selvaggi, Lucia Altucci, Giuseppe Paolisso, Michelangela Barbieri, Angela Nebbioso","doi":"10.1038/s41419-025-07982-6","DOIUrl":"10.1038/s41419-025-07982-6","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a leading cause of cancer-related deaths and obesity is a known risk factor for its development and poor prognosis. Adipose tissue (AT) actively contributes to CRC progression and cachexia. Here, we investigated molecular crosstalk between tumor cells and different visceral AT depots (normal, intra- and peri-tumoral), focusing on metabolic and (epi)genetic alterations. Using WGS analysis, we explored VAT role in CRC progression, demonstrating how its proximity to the tumor impacts metabolic and phenotypic changes. Intra-VAT (within 5 cm of lesion), closest to the tumor, underwent significant metabolic remodeling, characterized by upregulation of markers of the white-brown AT transition (UCP-1, TMEM26), lipid metabolism (PON3) and a reduction in adipocyte turnover (Pref-1, adiponectin). Peri-VAT (within 15 cm) and HVAT (over 15 cm) exhibited progressively fewer alterations, suggesting a gradient effect of tumor on surrounding AT. Intra-VAT displayed increased fibrosis (TGF-β, collagen) and cachexia-related markers (IL-8), and mutations in key oncogenes (KRAS, HLA, MET), highlighting a direct interaction between tumor cells and AT driving CRC progression. Mutations in genes such as KRAS, HLA, and PIK3CA were shared between CRC and its Intra-VAT, indicating potential biomarkers for tumor progression and immune evasion. miRNA analysis revealed upregulation of miR-21 and miR-92a in Intra-VAT, with circulating miR-92a correlating with increased body fat and decreased lean mass in CRC patients, suggesting their involvement in both local metabolic remodeling and systemic changes. Altered PON3 DNA methylation patterns were also observed, correlating with metabolic parameters. Our findings underscore AT's critical role in the CRC microenvironment as an active player in CRC progression and cachexia. Metabolic and genetic alterations decreased in VAT with increasing distance from the tumor. Intra-VAT may serve as a critical therapeutic target and biomarker for CRC progression, impacting surgical and postoperative strategies. Future studies should focus on targeting tumor-adipose crosstalk to improve treatment outcomes, including experimental validation of the identified genetic alterations and investigation of their functional roles in tumor progression and immune evasion.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"675"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF1 activity in photoreceptors drives type 3 neovascularization and retinal atrophy in a new mouse model of age-related macular degeneration.","authors":"Fredy Geiger, Thomas Heigl, Luca Merolla, Marcus Yong, Gabriele M Wögenstein, Larissa P Govers, Ioanna Tsioti, Antonia Fottner, Marijana Samardzija, Christian Grimm","doi":"10.1038/s41419-025-08028-7","DOIUrl":"10.1038/s41419-025-08028-7","url":null,"abstract":"<p><p>Morphological changes in the ageing eye impede oxygen delivery from the choroid to the outer retina causing tissue hypoxia, which activates a molecular response that adapts the transcriptomic fingerprint of the retina and retinal pigment epithelium (RPE). This response, orchestrated by hypoxia-inducible transcription factors (HIFs), leads to the production of pro-angiogenic factors and plays a critical role in the development and pathogenesis of age-related macular degeneration (AMD). To evaluate the specific contribution of HIF1 to this response we expressed a constitutively active form of HIF1A in rod photoreceptors of the adult mouse retina. This elicited a transcriptional response characterized by the upregulation of genes involved in cell death, inflammation and angiogenesis, all of which play an important role in AMD. The HIF1-mediated response in rods caused severe retinal degeneration, disruption of the RPE and retinal neovascularization. Pathological vessels originated from the deep vascular plexus and penetrated the RPE resembling type 3 macular neovascularization observed in over 20% of patients with neovascular AMD. Our study provides further evidence for the involvement of tissue hypoxia in the pathogenesis of AMD and highlights the potential of HIF1A as a therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"687"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)^~503.","authors":"Maria Vidal-Sabanés, Núria Bonifaci, Raúl Navaridas, Joaquim Egea, Mario Encinas, Ruth Rodriguez-Barrueco, Jose M Silva, Xavier Matias-Guiu, David Llobet-Navas, Xavier Dolcet","doi":"10.1038/s41419-025-08022-z","DOIUrl":"10.1038/s41419-025-08022-z","url":null,"abstract":"<p><p>Endometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGFβ-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the upregulation of several miRNAs caused by PTEN deficiency and/or TGFβ stimulation. The miR-424(322)^~503 cluster drew our attention due to its involvement in regulating apoptosis and proliferation. However, miR-424(322)^~503 cluster has a paradoxical role in cancer, exhibiting either oncogenic and tumor suppressive functions depending on cell type or context. To ascertain the function of miR-424(322)^~503 in endometrial carcinogenesis caused by PTEN deficiency, we generated a double Pten/miR-424(322)^~503 knock-out mice. We demonstrate that loss of miR-424(322)^~503 impairs proliferation of both wild type or Pten deficient endometrial organoids by interfering with growth factor and PI3K/AKT signaling. Furthermore, the absence of miR-424(322)^~503 restores TGFβ-induced apoptosis, which is otherwise compromised by PTEN deficiency. In vivo, Pten/miR-424(322)^~503 knock-out mice exhibit reduced endometrial cancer progression compared to Pten deficient mice through a cell-autonomous mechanism.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"705"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activating PIK3CA mutation promotes overgrowth of adipose tissue via inhibiting lipophagy in macrodactyly.","authors":"Yating Yin, Xiao Zhang, Shihui Lin, Zhibo Wang, Baoxing Tian, Xinyi Dai, Aiping Yu, Huixiao Li, Hailei Mao, Bin Wang","doi":"10.1038/s41419-025-08024-x","DOIUrl":"10.1038/s41419-025-08024-x","url":null,"abstract":"<p><p>Excessive proliferation and lipid accumulation of adipose tissue are the main pathological alterations in macrodactyly. Our previous studies found that macrodactyly exhibits abnormal lipid metabolism and inhibited autophagy, but the underlying mechanisms remain unclear. This study aims to investigate the regulatory mechanisms of autophagy in macrodactyly. The therapeutic impact and underlying mechanisms of autophagy on lipid accumulation, induced by a gain-of-function mutation of PIK3CA in macrodactyly, were assessed with respect to autophagy, lipid metabolism, oxidative stress, and deubiquitination. Autophagy deficiency resulting from PIK3CA mutation in macrodactyly led to excessive accumulation of adipose tissue. Lipid accumulation can be mitigated by inducing lipophagy of lipid droplets (LDs) in adipose derived stem cells of macrodactyly (Mac-ADSCs). The subsequent increase in free fatty acids (FFA) led to mitochondrial oxidative stress in Mac-ADSCs. Inducing autophagy exacerbated mitochondrial oxidative stress in Mac-ADSCs, thereby contributing to apoptosis. Additionally, the ablation of the deubiquitinase USP15 facilitated the degradation of LDs in Mac-ADSCs, through ubiquitin-dependent macrolipophagy. USP15 inhibitor reduced lipid accumulation in macrodactyly adipose tissue xenografts. In conclusion, activating PIK3CA mutation promotes excessive proliferation and lipid accumulation of Mac-ADSCs by inhibiting lipophagy. Targeted inhibition of USP15 may serve as a promising therapeutic approach for treating macrodactyly. A schematic illustrates that activating PIK3CA mutation promotes overgrowth of adipose tissue via inhibiting lipophagy in macrodactyly.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"686"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}