Cell Death & Disease最新文献

{"title":"Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis.","authors":"Jacek J Litewka, Mateusz D Szopa, Katarzyna Fryt, Monika A Jakubowska, Urszula Jankowska, Bozena Skupien-Rabian, Karolina Hajduk, Ewa Werner, Kinga B Stopa, Agnieszka A Kusiak, Daria Krzysztofik, Zbigniew Madeja, Pawel E Ferdek","doi":"10.1038/s41419-025-07881-w","DOIUrl":"10.1038/s41419-025-07881-w","url":null,"abstract":"<p><p>Acute pancreatitis (AP), a severe inflammatory disorder of the pancreas, lacks effective pharmacological treatment. The disease is primarily driven by necrosis of pancreatic acinar cells (PACs), which intensifies inflammation and organ injury. This study explores the potential of BCL2 inhibitors, specifically Navitoclax and Venetoclax, to shift cell death pathways from necrosis to apoptosis and thereby mitigate disease severity. Ex vivo models using cerulein or ethanol/palmitoleic acid (EtOH/POA) showed that both inhibitors significantly reduced necrosis, increased apoptosis, and improved PAC viability and ATP levels. In mouse models of AP, both drugs promoted apoptosis and decreased tissue necrosis, with Venetoclax showing superior efficacy and safety. Venetoclax markedly reduced disease severity in two AP models without affecting healthy tissue or inducing thrombocytopenia. In contrast, Navitoclax caused apoptosis even in healthy tissue and triggered thrombocytopenia. Additionally, both drugs attenuated pathological Ca²⁺ responses in PACs and upregulated the expression of Ca²⁺-binding proteins S100A8/A9 and the chemokine CCL8. The latter may mediate enhanced apoptotic clearance and limit secondary necrosis, supporting the therapeutic shift from necrosis to apoptosis. Proteomic analyses revealed extensive drug-induced remodeling. In the short-term AP model, both inhibitors altered expression of proteins linked to intracellular compartments and extracellular signaling, reflecting cellular adaptation. In CP, Navitoclax upregulated ECM and lysosomal proteins while downregulating ribosomal components-indicating intensified fibrosis and suppressed protein synthesis. Venetoclax had milder effects and did not worsen fibrosis. Despite Navitoclax's efficacy toward activated pancreatic stellate cells in vitro, it exacerbated fibrosis and tissue atrophy in CP in vivo, likely due to ongoing parenchymal damage and stellate cell activation. Together, these findings demonstrate that selective BCL2 inhibition with Venetoclax promotes apoptosis, reduces necrosis, and improves outcomes in AP, supporting its repurposing as a therapeutic strategy. However, BCL2 inhibition does not benefit CP and may aggravate fibrosis, underscoring the need for context-specific approaches.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"566"},"PeriodicalIF":9.6,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717654","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":"Peroxiredoxin 1 promotes intestinal inflammation by activating the NLRP3 inflammasome in macrophages through lysosomal disruption in Crohn's disease.","authors":"Shenglan Li, Qiuping Xia, Ying He, Wei Wu, Damu Tang, Zhenghao Deng, Zhijun Zeng, Sha Tu, Bo Chen, Lei Gu, Xinyi Yang, Yu Peng, Huixiang Yang, Zhangzhe Peng","doi":"10.1038/s41419-025-07898-1","DOIUrl":"10.1038/s41419-025-07898-1","url":null,"abstract":"<p><p>Damage-associated molecular patterns (DAMPs) are a cause of Crohn's disease (CD). Peroxiredoxin 1 (Prdx1), a newly identified DAMP, plays a critical role in organ injury with its potent proinflammatory properties. However, its specific role in CD remains unclear. Here, we identify serum Prdx1 as a DAMP involved in CD. Serum Prdx1 levels were significantly increased and positively correlated with the severity of intestinal inflammation in both CD patients and mice with experimental colitis. Genetic knockout of Prdx1 or administration of a Prdx1-neutralizing antibody attenuated colitis in mice, as evidenced by restoration of the colonic epithelium, improved disease activity, and reduced colonic inflammation. These protective effects were impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, Prdx1 exacerbated intestinal inflammation by promoting macrophage infiltration and subsequent cytokine production. Depletion of macrophages abolished the rPrdx1-mediated exacerbation of colitis. Further, rPrdx1 was internalized by macrophages, leading to lysosomal disruption and subsequent activation of the NLRP3 inflammasome. Pharmacological inhibition of NLRP3 effectively abrogated rPrdx1-induced exacerbation of colitis. In conclusion, serum Prdx1 promotes intestinal inflammation in CD at least in part by activating the NLRP3 inflammasome through lysosomal disruption in macrophages. These findings highlight the pathogenic role of Prdx1 in CD and reveal therapeutic potential of managing CD via neutralization of circulating Prdx1.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"565"},"PeriodicalIF":9.6,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717653","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 deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein.","authors":"Li Yang, Xiaoqin An, Shangzhu Yang, Xiaowen Lin, Ziyuan Chen, Qian Xue, Xi Chen, Yuan Wang, Ding Yan, Shirui Chen, Yuqing Fan, Daolin Tang, Wenfeng Yu, Jinbao Liu, Xin Chen","doi":"10.1038/s41419-025-07895-4","DOIUrl":"10.1038/s41419-025-07895-4","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype of invasive breast cancer characterized by limited treatment options and a poor prognosis. While ferroptosis, an iron-dependent form of regulated cell death, plays a role in tumor suppression, its specific molecular mechanisms in TNBC remain largely unexplored. In this study, we identify deubiquitinase USP24 as the most significantly altered enzyme among key deubiquitinating enzymes during ferroptosis in human TNBC cells. Silencing USP24 enhances ferroptosis-mediated tumor suppression in TNBC cells. Mechanistically, USP24 interacts directly with dihydroorotate dehydrogenase (DHODH) and deubiquitinates it, a process critical for maintaining coenzyme Q reduction and protecting cells from lipid peroxidation. Consistently, pharmacological inhibition of USP24 synergizes strongly with ferroptosis inducers in both in vitro and in vivo models via a DHODH-dependent pathway. These findings highlight USP24 as a potential therapeutic target to enhance ferroptosis sensitivity in TNBC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"564"},"PeriodicalIF":9.6,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717629","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":"Direct transdifferentiation of tumorigenic melanoma cells induces tumor cell reversion.","authors":"Yiman Wang, Ke Liu, Yuxin Zhang, Daniel Novak, Aniello Federico, Cai Xu, Sandra Horschitz, Marlene Vierthaler, Qian Sun, Nina Wang, Juliane Poelchen, Tamara Steinfass, Laura Hüser, Moritz Mall, Viktor Umansky, Jochen Utikal","doi":"10.1038/s41419-025-07863-y","DOIUrl":"10.1038/s41419-025-07863-y","url":null,"abstract":"<p><p>Melanoma is an aggressive skin cancer and highly lethal at advanced stages due to its high tumorigenicity and metastatic capacity. Changing the phenotype of cancer cells from one lineage to another, a process called transdifferentiation, leads to tumor cell reversion, which goes along with a drastic reduction of their tumorigenicity. Via ectopic overexpression of four neuronal transcription factors, we transdifferentiated melanoma cells into neuron-like cells expressing neuronal markers and showing a neuron-like morphology. Moreover, the tumorigenic and metastatic potential of transdifferentiated cells in vitro and in vivo was significantly reduced. Transdifferentiated cells were also more sensitive to radiotherapy compared with their parental counterparts. We conclude that transdifferentiation of cancer cells into terminally differentiated neuron-like cells might represent a prospective new therapeutic approach for the treatment of melanoma.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"563"},"PeriodicalIF":9.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717650","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":"Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis.","authors":"Zimei Cheng, Kexin Wang, Yixue Wang, Tingyan Liu, Jingjing Li, Yaodong Wang, Weiming Chen, Reyihangu Awuti, Hetian Zhou, Wenjia Tong, Zhenhao Yu, Yao Wang, Guoyun Su, Weiguo Yang, Yufeng Zhou, Guoping Lu, Caiyan Zhang","doi":"10.1038/s41419-025-07882-9","DOIUrl":"10.1038/s41419-025-07882-9","url":null,"abstract":"<p><p>Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynurenine (Kyn)/tryptophan (Trp) ratios, indicating increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, along with higher Kyn levels compared to controls. Moreover, Kyn levels were negatively correlated with thymus-to-thorax ratio. Further mechanistic analysis revealed that the enhanced expression of IDO1, induced by inflammatory signals, drives the accumulation of Kyn and subsequent activation of the aryl hydrocarbon receptor (AhR), triggering lipid oxidation-related gene transcription and ferroptosis in thymocytes during sepsis. Treatment with 1-methyltryptophan (IDO1 inhibitor) effectively restore thymic function and improve survival in septic mice. Our findings reveal a novel role for the IDO1/Kyn/AhR pathway in ferroptosis, suggesting that targeting this pathway may offer a promising therapeutic strategy for sepsis. Created with BioRender ( https://app.biorender.com/ ).</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"562"},"PeriodicalIF":9.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717651","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":"Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.","authors":"Tasnuva D Kabir, Samuel Beck, Lisa M Stuart, Ji Li, Rui Hou, Peiwen Liu, Shelby Margolius, Claire Kim, Yu Suk Choi, Edward R Bastow, Dianne J Beveridge, Lisa Spalding, Ziyi Li, Florent Ginhoux, Pierce Chow, Michael Phillips, Andrew D Redfern, George C Yeoh, Alistair Forrest, Andrew J Woo, Ankur Sharma, Jacob George, Geoffrey McCaughan, Peter J Leedman","doi":"10.1038/s41419-025-07887-4","DOIUrl":"10.1038/s41419-025-07887-4","url":null,"abstract":"<p><p>Resistance to multi-tyrosine kinase inhibitors (TKI) is a major clinical concern in advanced hepatocellular carcinoma (HCC). Herein, we aimed to uncover the mechanisms underlying pan-TKI resistance and to identify potential therapeutic targets. We used multiple TKI-resistant HCC cell lines to identify caveolin-1 (CAV1) as a key driver of therapeutic resistance. CAV1 downregulation induced apoptosis, inhibited metastasis and restored TKI sensitivity in both inherent and acquired TKI-resistant HCC cells. Mechanistically, in acquired TKI-resistant cells aberrant CAV1/STAT3/P70S6K signalling is required for their survival, motility, and invasiveness. CAV1 inhibition reduced expression of dormancy regulators E-cadherin, RAC1 and p21, enhanced cancer stemness markers, and disrupted downstream STAT3/P70S6K and AMPKα signalling pathways, prompting cancer cells to exit from dormancy and initiate autophagy-induced cell death. Furthermore, selective inhibition of AXL and FGFR4 downstream of the CAV1 pathway sensitized TKI-resistant cells to sorafenib and lenvatinib, respectively. In addition, microRNA-7-5p (miR-7) was identified as an endogenous regulator of CAV1; and miR-7's inhibitory effect on CAV1 and FGFR4 suppressed the STAT3/P70S6K pathway, promoted autophagy and triggered apoptosis in lenvatinib-resistant cells. Combination therapy using either lenvatinib or sorafenib and selective CAV1 inhibitors (e.g., siCAV1/miR-7), or AXL/FGFR4 inhibitors (e.g., BGB324/BLU9931) effectively overcame pan-TKI resistance. In HCC patient datasets, elevated CAV1 mRNA was observed in sorafenib non-responders, and single cell RNA-sequencing of HCC patient tumours revealed a rare population of CAV1+ cancer cells associated with recurrence. High CAV1 expression was specific to HBV+ HCC patients and independently predicted poor survival. Further, targeting of CAV1, AXL or FGFR4 effectively overcame TKI resistance in HCC patient derived organoids (PDOs). Our findings highlight a previously unrecognized role for CAV1-driven signalling in sustaining tumour dormancy, a critical and challenging therapeutic barrier underlying recurrence and pan-TKI resistance in HCC. Therapeutically targeting these pathways offer a promising and novel strategy to eliminate dormant tumour cells, thereby overcoming resistance and improving treatment outcomes.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"561"},"PeriodicalIF":9.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717652","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":"ATG7-deficient fibroblast promotes breast cancer progression via exosome-mediated downregulation of SCARB1.","authors":"Kangdi Li, Ting Liu, Zhihong Luo, You Yu, Yi Liu, Zhaoqing Zhang, Wenhua Li","doi":"10.1038/s41419-025-07885-6","DOIUrl":"10.1038/s41419-025-07885-6","url":null,"abstract":"<p><p>Although autophagy-related gene 7 (ATG7) acts as an E1-like activating enzyme and is essential for autophagy, it frequently performs broader roles involved in the modulation of diverse signaling pathways that affect cell proliferation, survival, migration and transformation. ATG7 is often downregulated in various cancers. However, the role of ATG7 in fibroblasts in regulating breast carcinoma remains poorly understood. Herein, we revealed that aberrantly low expression of ATG7 in breast stroma is clinically relevant to breast cancer progression. Loss of ATG7 expression results in fibroblasts acquiring the hallmarks of cancer-associated fibroblasts (CAFs), which finally promote the proliferation, metastasis of breast cancer in vivo and vitro. Detailed regulatory mechanisms showed that ATG7-deficient fibroblasts secrete a new miRNA (miR-6803b) and are then transported into breast cancer cells by exosomes. In breast cancer, miR-6803b targets the SCARB1 gene to inhibit its expression and then promote cancer cell metastasis, resulting in cancer progression. Thus, our results indicate that ATG7 expression in fibroblasts plays a vital role in regulating breast cancer tumorigenesis and progression by modifying stromal-epithelial crosstalk and remodeling the tumor microenvironment (TME). These results suggest that ATG7 can function as a tumor suppressor and represent a new candidate for prognosis and targeted therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"556"},"PeriodicalIF":9.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706337","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":"RB1 controls differentiation through positive regulation of phosphoglycerate mutases.","authors":"Susumu Kohno, Nobuyuki Okahashi, Yuansong Wan, Hai Yu, Yujiro Takegami, Paing Linn, Naoko Nagatani, Shunsuke Kitajima, Teruo Kawada, Fumio Matsuda, Hiroshi Shimizu, Chiaki Takahashi","doi":"10.1038/s41419-025-07850-3","DOIUrl":"10.1038/s41419-025-07850-3","url":null,"abstract":"<p><p>Most glycolytic enzymes are transcriptionally controlled by hypoxia-inducible factor-1α (HIF-1α) and/or MYC, however, phosphoglycerate mutases (PGAMs) are exceptional. Retinoblastoma tumor suppressor 1 (RB1) loss converts poorly spherogenic Trp53-null leiomyosarcoma cells to highly spherogenic. We determined a gene expression signature of RB1 loss-of-function in this setting and identified PGAM2 as a positive transcriptional target of RB1. Later, we found that RB1 positively controls PGAM1 as well in different tissues. RB1 deficiency induced a metabolic shift in the glycolytic pathway in a manner compatible with PGAM downregulation. Many of the metabolic features induced by RB1 loss were antagonized by PGAM overexpression. Furthermore, differentiation deficiency following RB1 loss was rescued by PGAM overexpression or pyruvate supplementation to varied degrees. These findings suggest that the RB1-PGAM1/2 axis at least partially controls RB1-dependent differentiation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"559"},"PeriodicalIF":9.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12290115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706339","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":"Retraction Note: CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9.","authors":"Yanli Zhang, Jianbing Hou, Shaomin Shi, Juan Du, Yudong Liu, Pan Huang, Qian Li, Lichao Liu, Huanrong Hu, Yacong Ji, Leiyang Guo, Yaqiong Shi, Yaling Liu, Hongjuan Cui","doi":"10.1038/s41419-025-07891-8","DOIUrl":"10.1038/s41419-025-07891-8","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"560"},"PeriodicalIF":9.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12290005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706340","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 accumulation of progerin underlies the loss of aortic smooth muscle cells in Hutchinson-Gilford progeria syndrome.","authors":"Paul H Kim, Joonyoung R Kim, Patrick J Heizer, Hyesoo Jung, Yiping Tu, Ashley Presnell, Julia Scheithauer, Rachel G Yu, Stephen G Young, Loren G Fong","doi":"10.1038/s41419-025-07853-0","DOIUrl":"10.1038/s41419-025-07853-0","url":null,"abstract":"<p><p>Hutchinson-Gilford progeria syndrome (HGPS) is caused by progerin, an internally truncated prelamin A that does not undergo the ZMPSTE24 processing step that releases prelamin A's farnesylated carboxyl terminus; consequently, progerin remains farnesylated. Progerin and full-length farnesyl-prelamin A are equivalent in their abilities to disrupt the nuclear lamina and trigger nuclear membrane ruptures and cell death, but they differ markedly in their abilities to cause arterial pathology. In HGPS mice (Lmna^G609G), progerin causes loss of aortic smooth muscle cells (SMCs) by 12 weeks, whereas farnesyl-prelamin A in Zmpste24^-/- mice does not trigger SMC loss-even at 21 weeks. In young mice, farnesyl-prelamin A levels in Zmpste24^-/- aortas and progerin levels in Lmna^G609G aortas are identical; however, progerin levels in Lmna^G609G aortas increase progressively with age, whereas farnesyl-prelamin A levels in Zmpste24^-/- aortas remain the same or decline. SMC loss in Zmpste24^-/- aortas occurs only with supraphysiologic levels of prelamin A synthesis (mimicking the accumulation of progerin). AKT activity (which mediates prelamin A phosphorylation and triggers prelamin A turnover) is lower in Lmna^G609G aortas than in wild-type or Zmpste24^-/- aortas. Our studies show that the progressive accumulation of progerin in the aorta underlies the arterial pathology in HGPS.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"557"},"PeriodicalIF":9.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12290114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706341","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}