Molecular Medicine最新文献

{"title":"MKRN1 degrades AGC1 to trigger chemotherapy resistance of colorectal Cancer.","authors":"Yixuan Wang, Mu Qiao, Jing Guo, Ying Xie, Meilin Hu, Xin Li, Sheng Wang, Jingjing Wang, Jingya Wang, Ziyi Peng, Mengqi Wang, Hao Cheng, Tiantian Li, Linchuang Jia, Danchen Su, Huanhuan Liu, Kexin Hu, Xinyang Li, Wenjing Li, Di Wu, Zhe Zhang, Jianing Han, Ruiyang Bai, Funan Zhou, Zhiqiang Liu","doi":"10.1186/s10020-025-01287-2","DOIUrl":"10.1186/s10020-025-01287-2","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"268"},"PeriodicalIF":6.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined treatment with antitoxin and 3,4-diaminopyridine improves survival outcomes after lethal botulinum neurotoxin challenge.","authors":"Sean W O'Brien, Brieana M Gregg, Adhirath Bollapragada, Patrick M McNutt","doi":"10.1186/s10020-025-01316-0","DOIUrl":"10.1186/s10020-025-01316-0","url":null,"abstract":"<p><p>Botulinum neurotoxins (BoNTs) are the most potent toxins known, causing life-threatening flaccid paralysis by blocking acetylcholine release at neuromuscular junctions. Clinical botulism results in respiratory failure, requiring prolonged artificial ventilation for survival. The only specific therapy is antitoxin, which neutralizes circulating toxin but cannot affect toxin within neurons, resulting in a narrow therapeutic window. Due to its high potency and lack of treatment options, large-scale BoNT exposures present profound risks to human life. Thus, there is an urgent need for rapidly acting symptomatic therapies that can reverse respiratory paralysis and sustain survival until resolution of toxin effects. We previously identified the FDA-approved, voltage-gated potassium channel blocker 3,4-diaminopyridine (3,4-DAP) as a fast-acting symptomatic treatment in preclinical botulism models. Here, we expand upon those findings by evaluating continuous infusion of 3,4-DAP in rats exposed to a typical range of BoNT/A doses. Infusion of clinically relevant doses of 3,4-DAP improved survival, reversed respiratory paralysis, and rapidly alleviated clinical signs at toxin doses substantially higher than previously studied. Therapeutic efficacy of 3,4-DAP correlated inversely with toxin exposure, consistent with its proposed mechanism of enhancing acetylcholine release from residual functional synaptic vesicle pools. 3,4-DAP treatment remained effective even when initiated at advanced stages of botulism, when antitoxin monotherapy provided no benefit, significantly extending the clinical treatment window. Combining 3,4-DAP infusion with antitoxin had robust effects on clinical outcomes, reversing clinical symptoms and improving survival compared to either treatment alone. Monitoring of body temperature further revealed that significant hypothermia precedes overt clinical symptoms, providing a novel biomarker of intoxication and treatment efficacy, as toxin-induced hypothermia resolved within hours after 3,4-DAP administration. Collectively, these findings provide robust preclinical evidence supporting clinical translation of 3,4-DAP as a symptomatic reversal agent for botulism, potentially transforming clinical management strategies for this lethal neurotoxin-induced disease.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"270"},"PeriodicalIF":6.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving Endoplasmic reticulum stress in mice with MASH.","authors":"Yi Chen, Kangjie Xie, Caiyang Chen, Xihui Wang, Chenchen Ma, Zhangxiang Huang, Yingfu Jiao, Weifeng Yu","doi":"10.1186/s10020-025-01332-0","DOIUrl":"10.1186/s10020-025-01332-0","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"269"},"PeriodicalIF":6.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the usefulness of C5 and C5AR1 as genetic biomarkers of IgA-mediated vasculitis.","authors":"Joao Carlos Batista-Liz, Vanesa Calvo-Río, María Sebastián Mora-Gil, María Teresa Leonardo, Ana Cristina Peñalba, Luis Martín-Penagos, Javier Narváez, Belén Sevilla-Pérez, José Luis Callejas-Rubio, Ligia Gabrie, Rafael Gálvez Sánchez, Luis Caminal-Montero, Paz Collado, María José Rodríguez Valls, Diego de Argila, Patricia Quiroga-Colina, Esther Francisca Vicente-Rabaneda, Esteban Rubio, Manuel León Luque, Juan María Blanco-Madrigal, Eva Galíndez-Agirregoikoa, Ricardo Blanco, Verónica Pulito-Cueto, Raquel López-Mejías","doi":"10.1186/s10020-025-01313-3","DOIUrl":"10.1186/s10020-025-01313-3","url":null,"abstract":"<p><strong>Background: </strong>IgA-mediated vasculitis (IgAV) is a complex inflammatory disease. Unravelling its genetic background would allow us to identify genetic biomarkers that may be used as additional tools in its daily management, helping to solve the clinical challenge that this vasculitis entails. C5 is a potent immune mediator that is proteolytically processed to generate C5a, a potent anaphylatoxin that exerts its function via C5aR1. C5 downstream variants (rs3761847 and rs10818488) have been recently related to IgAV pathogenesis. Additionally, C5a and C5aR1 dysregulation contributes to the development of inflammatory diseases, and, particularly, elevated C5a plasma levels have been observed in IgAV patients in the acute stage. Accordingly, we aimed to evaluate the influence of C5 and C5AR1 on the pathophysiology of IgAV.</p><p><strong>Methods: </strong>Eight C5 (rs10760128, rs74971050, rs4310279, rs7868761, rs10818495, rs10156396, rs3815467, and rs16910280) and three C5AR1 (rs10853784, rs11673071, and rs11670789) tag variants were genotyped in 342 Caucasian IgAV patients and 723 ethnically matched healthy controls.</p><p><strong>Results: </strong>No statistically significant differences were observed when C5 and C5AR1 frequencies were compared between IgAV patients and healthy controls. Likewise, similar C5 and C5AR1 frequencies were observed amongst IgAV patients stratified according to IgAV severity (presence/absence of nephritis). Furthermore, no C5 and C5AR1 differences were disclosed when IgAV patients were stratified according to demographic and clinical IgAV characteristics other than nephritis (age at disease onset, presence/absence of joint and gastrointestinal manifestations) and sex.</p><p><strong>Conclusions: </strong>Our results suggest that C5 and C5AR1 are not related to IgAV pathogenesis and, therefore, these genes may not be useful as IgAV genetic biomarkers.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"267"},"PeriodicalIF":6.4,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Plumbagin protects mice from lethal Sepsis by modulating immunometabolism upstream of PKM2.","authors":"Zhaoxia Zhang, Wenjun Deng, Rui Kang, Min Xie, Timothy Billiar, Haichao Wang, Lizhi Cao, Daolin Tang","doi":"10.1186/s10020-025-01329-9","DOIUrl":"10.1186/s10020-025-01329-9","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"265"},"PeriodicalIF":6.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyruvate kinase M2 activation maintains mitochondrial metabolism by regulating the interaction between HIF-1α and PGC-1α in diabetic kidney disease.","authors":"Jimin Park, Young Su Joo, Bo Young Nam, Gyuri Kim, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang, Seung Hyeok Han","doi":"10.1186/s10020-025-01320-4","DOIUrl":"10.1186/s10020-025-01320-4","url":null,"abstract":"<p><strong>Background: </strong>Pyruvate kinase isoform M2 (PKM2) activation has been suggested as a potential protective mechanism against kidney injury by improving mitochondrial dysfunction and anaerobic glycolysis. However, the underlying molecular mechanisms are unclear. Herein, we have demonstrated that PKM2 activation alleviates HIF-1α-mediated suppression of PGC-1α in diabetic kidney disease (DKD) models.</p><p><strong>Methods: </strong>In animal DKD study, db/db mice were intraperitoneally injected with TEPP-46, a PKM2 activator. In vitro, primary cultured renal tubular epithelial cells (RTECs) from C57BL/6 mice were exposed to high glucose (HG) conditions with and without TEPP-46. The interaction between HIF-1α and PGC-1α was investigated using HIF-1α overexpression and suppression.</p><p><strong>Results: </strong>Our findings in db/db mice kidneys unveiled a reduced PKM2 activation, aberrant glycolysis, impaired fatty acid oxidation, and decreased mitochondrial mass, integrity, and function under diabetic conditions. These changes were accompanied by increased HIF-1α and decreased PGC-1α levels. Furthermore, diabetic kidney exhibited increased fibrosis and apoptosis markers. Notably, direct PKM2 activation by TEPP-46 treatment counteracted the perturbed energy metabolism, restored mitochondrial function, and reduced cell death. Similar effects were also observed in HG-treated RTECs upon TEPP-46 intervention. Mechanistically, our chromatin immunoprecipitation assay revealed that HIF-1α directly bound to the regulatory region of the Ppargc1a promoter, and this interaction was inversely dependent on PKM2 activation. Moreover, Hif1ɑ overexpression suppressed Ppargc1a and triggered aberrant energy metabolism, mitochondrial dysfunction, and apoptosis. These changes were reversed by HIF-1α suppression.</p><p><strong>Conclusion: </strong>Our study highlights the role of PKM2 activation in restoring impaired mitochondrial metabolism and function by modulating HIF-1α and PGC-1α interactions in DKD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"266"},"PeriodicalIF":6.4,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caffeic acid phenethyl ester protects renal tubular epithelial cells against ferroptosis in diabetic kidney disease via restoring PINK1-mediated mitophagy.","authors":"Ying Lu, Ye Zhu, Sheng Feng, Qifei Cong, Sixia Chen, Ying Zeng, Kai Song, Ji Hu","doi":"10.1186/s10020-025-01318-y","DOIUrl":"10.1186/s10020-025-01318-y","url":null,"abstract":"<p><p>Mounting evidence indicates that renal tubular ferroptosis plays a crucial role in the progression of diabetic kidney disease (DKD). Caffeic acid phenethyl ester (CAPE), derived from propolis, a precious resinous substance synthesized by various bee species, has garnered broad attention in biomedical research. This study aims to explore the mechanism by which CAPE protects renal tubular epithelial cells (TECs) against ferroptosis in DKD. DBA/2J mice were administered streptozotocin (STZ) by intraperitoneal injection, fed a high-fat diet (HFD) and treated with CAPE. The findings revealed significant changes in ferroptosis markers. In diabetic mice and TECs under high-glucose (HG) conditions, levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased, while transferrin receptor 1 (TFR1) increased. These changes were accompanied by a reduction in antioxidant capability and the accumulation of malondialdehyde (MDA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the intersection targets of CAPE and ferroptosis were mainly located in the mitochondria and exhibited high enrichment values in mitophagy. Further investigations revealed that HG induced a depolarization of mitochondrial membrane potential and an excessive level of mitochondrial reactive oxygen species (ROS), accompanied by defective mitophagy. The administration of CAPE inhibited exacerbated ferroptosis and rescued defective mitophagy induced by DKD. In addition, CAPE restored PTEN-induced putative kinase 1 (PINK1) levels, which were markedly diminished in the kidneys of DKD mice and TECs subjected to HG. Molecular docking simulation experiments suggested that CAPE is steadily bound to the PINK1 active pocket. Cellular Thermal Shift Assay (CETSA) and Drug Affinity Responsive Target Stability assay (DARTS) showed that CAPE enhances the thermal stability of the PINK1 protein within a specific temperature range and protects the PINK1 protein from degradation by proteolytic enzymes. These results confirm that CAPE interacts with PINK1 as its specific target. However, the positive outcomes of CAPE treatment on ferroptosis were nullified by the PINK1 siRNA. This research indicates that CAPE has potential therapeutic benefits for DKD by protecting renal TECs against ferroptosis via rescuing PINK1-mediated mitophagy. These findings suggest that CAPE shows potential as a therapeutic agent to prevent tubular injury in DKD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"264"},"PeriodicalIF":6.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tirzepatide mitigates Stroke-Induced Blood-Brain barrier disruption by modulating Claudin-1 and C/EBP-α pathways.","authors":"Duozi Wang, Jianhong Wang, Binghu Li, Shu Yang, Fuqiang Guo, Bo Zheng, Jian Wang","doi":"10.1186/s10020-025-01312-4","DOIUrl":"10.1186/s10020-025-01312-4","url":null,"abstract":"<p><strong>Background: </strong>Stroke is a major cause of disability and mortality worldwide, with ischemic stroke (IS) being the most common form. The blood-brain barrier (BBB) plays a critical role in protecting the brain, and its dysfunction after stroke exacerbates neuronal damage. Therefore, restoring BBB integrity is a promising therapeutic strategy. Tirzepatide (TZP), a dual GLP-1 and GIP receptor agonist, has demonstrated neuroprotective effects, but its role in BBB restoration post-stroke remains unclear.</p><p><strong>Objective: </strong>This study aims to evaluate the potential of TZP in preventing BBB dysfunction and restoring its integrity in ischemic stroke models.</p><p><strong>Methods: </strong>Using a middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke, we assessed the effects of TZP on neurological deficits, BBB permeability, and the expression of tight junction (TJ) proteins, particularly Claudin-1. In vitro, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate ischemic conditions. The involvement of C/EBP-α, a key transcription factor regulating TJ proteins, was also investigated.</p><p><strong>Results: </strong>TZP treatment significantly improved neurological scores and reduced BBB permeability in MCAO mice. It also restored Claudin-1 expression, which was downregulated in stroke conditions. In vitro, TZP reduced endothelial permeability and enhanced Claudin-1 expression in OGD/R-treated HBMVECs. Silencing C/EBP-α abolished the protective effects of TZP on both BBB integrity and Claudin-1 expression, indicating that C/EBP-α signaling is crucial for TZP's action.</p><p><strong>Conclusion: </strong>TZP ameliorates BBB dysfunction and protects against ischemic stroke by activating C/EBP-α signaling and restoring Claudin-1-mediated tight junction integrity. These findings suggest that TZP holds promise as a therapeutic agent for stroke, offering a novel strategy for maintaining BBB function and reducing neuronal damage. Further studies are needed to explore the detailed mechanisms underlying TZP's neuroprotective effects and its clinical potential in stroke therapy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"263"},"PeriodicalIF":6.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of prenatal amoxicillin exposure at different doses, stages, and courses on offspring ovarian development.","authors":"Jing Huang, Yating Li, Ming Zhang, Tiancheng Wu, Yuanzhen Zhang, Hui Wang","doi":"10.1186/s10020-025-01322-2","DOIUrl":"10.1186/s10020-025-01322-2","url":null,"abstract":"<p><strong>Background: </strong>Amoxicillin, a commonly used broad-spectrum penicillin antibiotic in pregnancy, has sparked controversy regarding its impact on fetal growth and development. There remains a lack of systematic research on the specific influence of prenatal amoxicillin exposure (PAmE) on the ovarian development of the offspring, as well as the precise \" toxicity windows \".</p><p><strong>Methods: </strong>We established PAmE mouse models at different stages [(gestational day, GD) 10-12, GD13-15 or GD16-18], doses (75, 150 or 300 mg/kg·d), and courses (single/multiple courses). On GD18, fetal serum and ovaries were collected to assess changes in serum estradiol levels and evaluate ovarian morphology, pregranulosa cell function, and oocyte-related parameters.</p><p><strong>Results: </strong>PAmE led to pathological damage in fetal mouse ovaries, characterized by disrupted germ cell cysts and reduced the number of germ cells. Cell proliferation was enhanced while apoptosis was reduced. Moreover, PAmE upregulated the expression of pregranulosa cell steroid synthesis-related genes (e.g., Sf1, Star, P450scc) in the fetal ovaries, particularly in the high-dose groups at all gestational stages. The expression of the oocyte marker gene Figlα increased in all PAmE groups, while follicle development-related genes (Nobox and Bmp15) were downregulated, particularly during early to mid-pregnancy and in the single-course exposure groups. Further investigation revealed that PAmE enhanced IGF1 expression in fetal ovaries and inhibited the Pten-Akt-Foxo3a signaling pathway.</p><p><strong>Conclusions: </strong>Amoxicillin exhibits ovarian developmental toxicity, influencing fetal ovarian cell proliferation, apoptosis, pregranulosa cell estrogen synthesis, oocyte numbers, and follicle assembly. This study provides evidence guiding the rational use of amoxicillin in pregnancy and assessing potential ovarian development risks.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"261"},"PeriodicalIF":6.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depot-specific metabolic and inflammatory profiles in perirenal and renal sinus adipose tissue.","authors":"Maria J Pereira, Argyri Mathioudaki, Susanne Hetty, Amir Sedigh, Jan W Eriksson, Maria K Svensson","doi":"10.1186/s10020-025-01323-1","DOIUrl":"10.1186/s10020-025-01323-1","url":null,"abstract":"<p><strong>Background: </strong>Alterations in kidney-associated adipose tissue depots, specifically renal sinus (RSAT) and perirenal adipose tissue (PRAT), may contribute to metabolic, cardiovascular, and chronic kidney diseases. We compared transcriptomic profiles and phenotypes, including adipocyte size, glucose uptake, and insulin action in RSAT and PRAT from healthy individuals.</p><p><strong>Methods: </strong>Subcutaneous (SAT), omental (OAT) and renal adipose tissue biopsies were collected from healthy kidney donors (20 women, 20 men; BMI 20 to 36 kg/m²). Adipocyte size and basal and insulin-stimulated glucose uptake rate were measured in isolated adipocytes. Transcriptomic profiling and immune cell composition estimates (RNA seq, n = 30), were performed to evaluate differences between PRAT and RSAT, with OAT as a benchmark.</p><p><strong>Results: </strong>PRAT exhibited significantly larger adipocytes and higher insulin-stimulated glucose uptake than RSAT. Of 1113 significantly differentially expressed genes (DEGs) (PRAT: 571 down- and 542 upregulated), thermogenic and metabolic genes (UCP1, CIDEA, and CKMT1B) were enriched in PRAT, while inflammation-related genes (NFKBIA, BIRC3, and IRF1) in RSAT. Pathway analysis indicated activation of metabolic pathways (TCA cycle and oxidative phosphorylation), in PRAT, which contrasts with the immune and inflammatory pathways in RSAT and OAT. Immune cell gene signatures revealed an anti-inflammatory environment in PRAT (eosinophils and activated NK cells), and a pro-inflammatory profile in RSAT (M0 macrophages). Immunohistochemistry confirmed higher CD68- and IL1B-positive cells in RSAT than in PRAT. When overweight individuals were compared to lean, genes related to the VEGF signaling were upregulated in PRAT and Ras signaling in RSAT. Additionally, metabolic pathways linked to the TCA cycle as well as carbon and fatty acid metabolism were downregulated.</p><p><strong>Conclusions: </strong>The different kidney-associated adipose tissue depots exhibit distinct gene expression and functional profiles. PRAT displays higher expression of thermogenic markers and less inflammatory profile compared to RSAT and also OAT. In contrast, RSAT exhibits an inflammatory and macrophage-enriched profile, more closely resembling OAT. This study highlights the heterogeneity of the kidney-associated adipose tissue depots and could suggest that an excessive amount of RSAT may impact development of metabolic, cardiovascular, and chronic kidney diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"262"},"PeriodicalIF":6.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}