American journal of physiology. Cell physiology最新文献

{"title":"AI-assisted semiquantitative measurement of murine bleomycin-induced lung fibrosis using in vivo micro-CT: an end-to-end approach.","authors":"Hanlin Cheng, Tianyun Gao, Yichen Sun, Feifei Huang, Xiaohui Gu, Chunjie Shan, Shouhua Luo, Bin Wang","doi":"10.1152/ajpcell.00604.2024","DOIUrl":"10.1152/ajpcell.00604.2024","url":null,"abstract":"<p><p>Small animal models are crucial for investigating idiopathic pulmonary fibrosis (IPF) and developing preclinical therapeutic strategies. However, there are several limitations to the quantitative measurements used in the longitudinal assessment of experimental lung fibrosis, e.g., histological or biochemical analyses introduce interindividual variability, whereas image-derived biomarker has yet to directly and accurately quantify the severity of lung fibrosis. This study investigates artificial intelligence (AI)-assisted, end-to-end, semiquantitative measurement of lung fibrosis using in vivo micro-computed tomography (CT). Based on the bleomycin (BLM)-induced lung fibrosis mouse model, the AI model predicts histopathological scores from in vivo micro-CT images, directly correlating these images with the severity of lung fibrosis in mice. Fibrosis severity was graded by the Ashcroft scale: none (0), mild (1-3), moderate (4-5), and severe (≥6). The overall accuracy, precision, recall, and F1 scores of the lung fibrosis severity-stratified 3-fold cross validation on 225 micro-CT images for the proposed AI model were 92.9%, 90.9%, 91.6%, and 91.0%, respectively. The overall area under the receiver operating characteristic curve (AUROC) was 0.990 [95% confidence interval (CI): 0.977, 1.000], with AUROC values of 1.000 for none (100 images, 95% CI: 0.997, 1.000), 0.969 for mild (43 images, 95% CI: 0.918, 1.000), 0.992 for moderate (36 images, 95% CI: 0.962, 1.000), and 0.992 for severe (46 images, 95% CI: 0.967, 1.000). Preliminary results indicate that AI-assisted, in vivo micro-CT-based semiquantitative measurements of murine are feasible and likely accurate. This novel method holds promise as a tool to improve the reproducibility of experimental studies in animal models of IPF.<b>NEW & NOTEWORTHY</b> To the best of our knowledge, this study is the first attempt to establish a direct link between radiological images and the severity of experimental lung fibrosis using artificial intelligence (AI). The proposed method, which accurately quantifies the degree of lung fibrosis in longitudinal observations of experimental animals, has the potential to serve as a new tool to improve the reproducibility of experimental studies in animals with idiopathic pulmonary fibrosis (IPF).</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C659-C674"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681865","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":"Contribution of NLRP3-GSDMD axis to PDGF-BB-induced vascular smooth muscle cell phenotypic transition.","authors":"Yun-Ting Wang, Alexandra K Moura, Rui Zuo, Yinglu Guan, Emily A Lee, Jenny Z Hu, Kiana Roudbari, Zhengchao Wang, Mi Wang, Pin-Lan Li, Jiukuan Hao, Xiang Li, Yang Zhang","doi":"10.1152/ajpcell.00226.2025","DOIUrl":"10.1152/ajpcell.00226.2025","url":null,"abstract":"<p><p>Intimal hyperplasia, a pathological form of vascular remodeling, is a hallmark of several cardiovascular diseases, including restenosis following angioplasty. Vascular smooth muscle cell (VSMC) phenotypic transition plays a critical role in the development of vascular intimal hyperplasia. This study investigates the role of the NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and its downstream effector, gasdermin D (GSDMD), in regulating VSMC phenotypic transition and their implications in the development of intimal hyperplasia. In primary cultured VSMCs, platelet-derived growth factor BB (PDGF-BB) stimulated activation of the NLRP3-GSDMD axis, promoting inflammation, proliferation, and migration. Pharmacological inhibition of the inflammasome with the caspase-1 inhibitor YVAD significantly attenuated PDGF-BB-induced GSDMD activation and lactate dehydrogenase release. Furthermore, silencing the <i>Gsdmd</i> gene effectively blocked PDGF-BB-induced VSMC proliferation, migration, and inflammatory responses. In vivo, intimal hyperplasia was modeled by performing carotid artery ligation in hypercholesterolemic mice. In <i>Nlrp3</i>^+/+ mice, vascular injury led to increased inflammasome and GSDMD activation, enhanced pyroptosis, elevated vascular inflammation, macrophage infiltration, and a shift to a synthetic VSMC phenotype, primarily within the VSMC-rich intimal region. In contrast, these pathological changes were significantly attenuated in <i>Nlrp3</i>^-/- mice. These findings provide novel insights into the critical role of the NLRP3-GSDMD axis in VSMC phenotypic transition and vascular injury-induced intimal hyperplasia, suggesting that targeting this pathway may offer a promising therapeutic strategy for cardiovascular diseases characterized by intimal hyperplasia.<b>NEW & NOTEWORTHY</b> This study reveals that the NLRP3-GSDMD axis drives PDGF-BB-induced dedifferentiation transition and inflammation of vascular smooth muscle cells (VSMCs), contributing to intimal hyperplasia. These findings identify NLRP3-GSDMD signaling as a novel driver of pathological vascular remodeling and a potential therapeutic target for intimal hyperplasia-associated cardiovascular diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C682-C698"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681867","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":"Retraction for Wang and Gao.","authors":"","doi":"10.1152/ajpcell.00481.2024","DOIUrl":"10.1152/ajpcell.00481.2024","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C480"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514393","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":"Making sense of MYC in skeletal muscle: location, duration, and magnitude.","authors":"Ronald G Jones, Sebastian Edman, Nathan Serrano, Yuan Wen, John J McCarthy, Christopher S Fry, Ferdinand von Walden, Kevin A Murach","doi":"10.1152/ajpcell.00528.2025","DOIUrl":"10.1152/ajpcell.00528.2025","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C624-C629"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706042","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":"Asprosin attenuates diabetic cardiomyopathy through inhibiting autophagy mediated by AMPK/mTOR/ULK1 pathway.","authors":"Yuan Wang, Wentao Liu, Chen Liu, Zhitong Zhou, Sheng Chen, Qianqian Huang, Li Wang, Guohua Zeng, Qiren Huang","doi":"10.1152/ajpcell.01006.2024","DOIUrl":"10.1152/ajpcell.01006.2024","url":null,"abstract":"<p><p>Aberrant autophagy mediated by AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51 like kinase 1 (ULK1) pathway (a canonical autophagy pathway) plays important roles in diabetic cardiomyopathy (DCM). Asprosin (ASP) secreted by white adipose tissue involves in systemic metabolism disorders. However, its role in DCM remains poorly understood. Therefore, the purpose of this study was to investigate its roles and underlying mechanisms in the DCM from the perspective of autophagy and apoptosis. In the in vivo experiments, we observed the effects of ASP deficiency (ASP^-/-) or ASP intervention on cardiac function, fibrosis, autophagy, and apoptosis in a diabetes mellitus (DM) mouse model induced by high-fat feeding and streptozotocin (STZ) injection; in the in vitro experiments, we evaluated the effects of ASP intervention with or without 3-methyladenine (3-MA) (autophagy inhibitor) or siAMPK in a H9c2 model injured by high glucose (HG). Our results show that ASP intervention attenuates the myocardial injury induced by DM (<i>P</i> < 0.05) and HG (<i>P</i> < 0.05). In addition, the autophagy level markedly increases (<i>P</i> < 0.05) in diabetic mice, and ASP deficiency worsens the increase induced by DM (<i>P</i> < 0.05). In contrast, ASP intervention alleviates overautophagy induced by DM (<i>P</i> < 0.05) or HG (<i>P</i> < 0.05). Mechanistically, the protective effect of ASP against myocardial injury is through inhibiting the overautophagy mediated by AMPK/mTOR/ULK1 pathway (<i>P</i> < 0.05). Taken together, the findings suggest that ASP would be a potential therapeutic target and the recombinant ASP might be a promising candidate to treat metabolism-associated CVD. Although the findings would present a promise for the treatment of DCM, it is worth noting that the mouse model used fails to fully mimic the human DCM pathophysiology.<b>NEW & NOTEWORTHY</b> We demonstrated for the first time that asprosin (ASP) has protective effects against diabetic cardiomyopathy. We found that ASP could stimulate the AMPK/mTOR/ULK1 pathway to reduce the level of autophagy and apoptosis of cardiomyocytes, thereby maintaining the normal physiological function of the heart.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C377-C394"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493410","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":"Mitochondrial ATP-sensitive K⁺ channels (MitoK_ATP) regulate brown adipocyte differentiation and metabolism.","authors":"Osvaldo Rodrigues Pereira, Julian D C Serna, Camille C Caldeira da Silva, Henrique Camara, Sean D Kodani, William T Festuccia, Yu-Hua Tseng, Alicia J Kowaltowski","doi":"10.1152/ajpcell.00070.2025","DOIUrl":"10.1152/ajpcell.00070.2025","url":null,"abstract":"<p><p>Brown adipose tissue (BAT) plays a central role in mammalian nonshivering thermogenesis, dissipating mitochondrial membrane potentials through the activity of uncoupling protein UCP1 to release heat. Inner membranes of mitochondria are known to be permeable to potassium ions (K⁺), which enter the matrix either through ATP-sensitive channels (MitoK_ATP) or leakage across the bilayer driven by inner membrane potentials. Mitochondrial K⁺ influx is associated with increased osmotic pressure, promoting water influx and increasing matrix volume. Since BAT mitochondria have lower inner membrane potentials due to uncoupling protein 1 (UCP1) activity, we hypothesized this could involve compensatory changes in MitoK_ATP activity and thus tested MitoK_ATP involvement in brown adipocyte activities under basal and stimulated conditions. We find that cold exposure and adrenergic stimulation in mice modulate BAT MitoK levels, the channel portion of MitoK_ATP. Genetic ablation of the gene that codes for the pore-forming subunit of MitoK_ATP in human preadipocytes decreased cellular respiration and proliferation, compromising differentiation into mature adipocytes. In mouse cell lines, the absence of the protein limited cellular oxygen consumption in the precursor stage but not in mature adipocytes. Interestingly, inhibition of MitoK_ATP in mature adipocytes increased adrenergic-stimulated oxygen consumption, indicating that shutdown of this pathway is important for full BAT thermogenesis. Similarly, MitoK_ATP inhibition increased oxygen consumption in BAT mitochondria isolated from mice treated with the β3 adrenergic receptor agonist CL316,243. Overall, our results suggest that the activity of MitoK_ATP regulates differentiation and metabolism of brown adipocytes, impacting thermogenesis.<b>NEW & NOTEWORTHY</b> Brown fat cells are important to maintain a healthy body weight by promoting mitochondrial uncoupling. Here, we demonstrate that mitochondrial ATP-sensitive potassium channels (MitoK_ATP) have important roles both in the differentiation of brown fat cells and in the activation of energy-dissipating uncoupling in this tissue.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C574-C584"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607153","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":"Postexercise ketone monoester administration concomitant with glucose stimulates glycogen repletion in soleus muscle in mice.","authors":"Yumiko Takahashi, Tatsuya Matsumoto, Wenxin Wang, Takeru Inaba, Shin Terada, Hideo Hatta","doi":"10.1152/ajpcell.00311.2025","DOIUrl":"10.1152/ajpcell.00311.2025","url":null,"abstract":"<p><p>Although our group has demonstrated that the administration of β-hydroxybutyrate, a major type of ketone body, stimulated postexercise glycogen repletion in isolated skeletal muscle, investigations of the effects of ketone supplementation on postexercise muscle glycogen repletion in vivo have obtained conflicting results. Here, we investigated the effects of an oral intake of the ketone monoester [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate] on postexercise glycogen repletion in mouse skeletal muscles. Ten-week-old male Institute of Cancer Research mice ran on a treadmill at 25 m/min speed for 60 min. Immediately after the exercise, the mice were orally administered a solution containing 1.0 g/kg body wt (BW) of glucose and 2.0 g/kg BW of ketone monoester (KE solution) or a solution containing glucose and 1.11 g/kg BW of triolein for the adjustment of total calories to match the KE solution's (Con solution). The KE-treated group showed significantly lower postadministration blood glucose concentrations and higher plasma insulin concentrations compared with those of the Con-treated group. The KE-treated group showed a 42.1% higher glycogen concentration in soleus muscle (slow-twitch fiber-dominant) at 60 min postadministration compared with that of the Con group. There was no significant between-group difference in the glycogen concentration in the plantaris muscle (fast-twitch fiber-dominant). The KE-treated group's soleus muscle also showed significantly lower phosphorylation levels of AMP-activated kinase Thr¹⁷² at 30 min postexercise compared with the level immediately postexercise. These results demonstrated that a postexercise administration of ketone monoester enhanced glycogen repletion, particularly in slow-twitch fiber-dominant muscle.<b>NEW & NOTEWORTHY</b> This is the first study to compare the effects of postexercise ketone body intake on glycogen repletion in fast-twitch fiber- and slow-twitch fiber-dominant muscles. A postexercise administration of ketone monoester together with glucose enhanced the glycogen repletion in murine slow-twitch fiber-dominant muscle but not in fast-twitch fiber-dominant muscle. The ketone monoester intake also elicited higher insulin levels in plasma and lower AMPK phosphorylation levels in soleus muscle during the postexercise phase.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C366-C376"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493412","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":"Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.","authors":"Andra Grigorescu, Anca-Lelia Riza, Ioana Streata, Mihai G Netea","doi":"10.1152/ajpcell.00153.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00153.2025","url":null,"abstract":"<p><p>Trained immunity (TRIM) is the process through which the innate immune system undergoes memory-like epigenetic and metabolic reprogramming following an earlier infectious challenge. Trained immunity can be induced, in a similar fashion to microbial structures, by various endogenous compounds: oxidized low-density lipoproteins, lipoprotein(a), glucose and uric acid, and monosodium urate. Lipids, glucose, and protein metabolic dysfunction have the potential to perpetuate a proinflammatory feedback loop through the induction of maladaptive trained immunity programs, as shown in cardiovascular diseases, diabetes, and hyperuricemia. Molecular mechanisms leading to TRIM are susceptible to homeostatic disruptions of advanced age, and maladaptive TRIM may be the link between immune aging and age-associated pathologies. The present review discusses the current knowledge on metabolic pathways in adaptive and maladaptive trained immunity and its deleterious consequences of inappropriate activation during aging. Finally, we discuss how several dietary patterns modulate immunometabolism and influence trained immunity in aging.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"329 2","pages":"C456-C470"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688644","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":"The Evolution of Chemical Biology into Translational Physiology and Precision Medicine.","authors":"Merry L Lindsey, Frank L Douglas","doi":"10.1152/ajpcell.00438.2025","DOIUrl":"10.1152/ajpcell.00438.2025","url":null,"abstract":"<p><p>Pharmaceutical research has undergone significant transformation over time, particularly in the development of potent compounds that target specific physiological mechanisms. The need to demonstrate clinical benefit posed challenges. These challenges led to the rise of translational physiology and precision medicine aided by the development of the chemical biology platform. The chemical biology platform is an organizational approach to optimize drug target identification and validation and improve safety and efficacy of biopharmaceuticals. The platform achieves this goal through emphasis on understanding the underlying biological processes and leveraging knowledge gained from the action of similar molecules on these biological processes. The platform connects a series of strategic steps to determine whether a newly developed compound could translate into clinical benefit using translational physiology. Translational physiology examines biological functions across multiple levels, from molecular interactions to population-wide effects, and has been deeply influenced by the advancement of the chemical biology platform. Unlike traditional trial-and-error methods, by leveraging systems biology techniques, such as proteomics, metabolomics and transcriptomics, chemical biology prioritizes targeted selection to enhance drug discovery. This historical review explores the evolution of the chemical biology platform and its role in precision medicine, highlighting its continued influence in both academic research and pharmaceutical innovation. By fostering a mechanism-based approach to clinical advancement, chemical biology remains a critical component in modern drug development. Additionally, understanding the history and integrative nature of this platform is essential for training the next generation of researchers in the design of experimental studies that effectively incorporate translational physiology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641559","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":"Biological and metabolomic insights into RACGAP1-mediated growth and progression of clear cell renal cell carcinoma.","authors":"Wanyi Li, Lingling Gan, Wenting Zang, Yan Chen, Bei Xu","doi":"10.1152/ajpcell.00066.2025","DOIUrl":"10.1152/ajpcell.00066.2025","url":null,"abstract":"<p><p>Rac-GTPase-activating protein 1 (RACGAP1) is a member of the Rho GTPase-activating protein (GAP) family, which is involved in the process of cytokinesis. But its precise function in clear cell renal cell carcinoma (ccRCC) has not been extensively investigated. In this study, we found that RACGAP1 was regulated by centrosomal protein CEP55 and markedly facilitated the growth and progression of ccRCC in vitro and in vivo. In addition, RACGAP1 knockdown induces G1 phase arrest, resulting in mitotic disorder and subsequent apoptosis. These findings indicated that RACGAP1, a cell cycle-related gene, is crucial for the survival and growth of ccRCC. Furthermore, renal cancer is closely associated with metabolic processes. As demonstrated by our serum-targeted metabolomics study, RACGAP1 dysfunction altered the levels of multiple amino acids/amino acid derivatives, acylcarnitines, fatty acids/acyls, nucleotides, and their metabolites. Spatial metabolomics data further confirmed that downregulation of RACGAP1 expression could inhibit ccRCC growth not only by reprogramming fatty acid and nucleotide metabolism but also by interfering with lipid metabolism. More importantly, we detected higher levels of glutamine, acylcarnitines, and lipids in the tumor margin region, suggesting intratumor metabolic heterogeneity in ccRCC. In conclusion, this study elucidated the biological function of RACGAP1 in promoting ccRCC progression and revealed the regulatory mechanism of RACGAP1 in interfering with metabolic pathways from the perspective of multidimensional metabolomics. These findings will provide new targets and a theoretical basis for the treatment of RCC.<b>NEW & NOTEWORTHY</b> We have demonstrated for the first time that CEP55 directly regulated RACGAP1 expression, and downregulation of RACGAP1 blocked ccRCC mitotic division at the G1 phase and induced apoptosis. Targeted and spatial metabolomics analyses showed that RACGAP1 disruption altered levels of multiple metabolites and inhibited ccRCC growth by reprogramming fatty acid, nucleotide, and lipid metabolism. Importantly, spatial imaging of metabolites uncovered intratumor metabolic heterogeneity in ccRCC, providing novel insights into the metabolic landscape of this malignancy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C283-C297"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309357","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}