Molecular Medicine最新文献

{"title":"METTL3/YTHDC1 axis-mediated m⁶A modification of Foxo1 mRNA promote endothelial autophagic apoptosis in diabetic atherosclerosis.","authors":"Yujia Zhao, Longjia Tang, Hongtian Zhang, Xu Liu, Haonan Zhang, Ying Zhao, Legao Chen, Xiaoting Chen, Xiaohong Wu","doi":"10.1186/s10020-026-01543-z","DOIUrl":"10.1186/s10020-026-01543-z","url":null,"abstract":"<p><strong>Background and aims: </strong>Endothelial dysfunction is critical in diabetic angiopathy. While our previous study established role of FOXO1 in mediating advanced glycation end products (AGEs)-induced autophagic apoptosis in human aortic endothelial cells (HAECs), the potential mechanism of N6-methyladenosine (m⁶A) modification in this process remains unknown.</p><p><strong>Methods: </strong>RNA-m⁶A methylation and methyltransferase-like 3 (METTL3) / YTH domain containing 1 (YTHDC1) expression in carotid plaques of diabetic patients and aortic plaques of diabetic apoe^-/- mice induced by STZ were detected by quantitative kit, immunohistochemical staining and immunofluorescence co-localization respectively. METTL3 and YTHDC1 were knocked down to observe changes in the m⁶A methylation status and expression of FOXO1. FOXO1 was overexpressed in METTL3-deficient HAECs to assess autophagic flux and apoptosis. Finally, the effect of METTL3 on atherosclerotic plaque formation was validated using endothelial cell-specific METTL3 knockout diabetic mice.</p><p><strong>Results: </strong>RNA m⁶A modification levels and the expression of the METTL3/YTHDC1 were upregulated in human diabetic carotid plaques, mouse aortic plaques, and AGEs-treated HAECs, accompanied by increased m⁶A methylation of Foxo1 mRNA. METTL3 mediates the AGEs-induced increase in m⁶A modification of Foxo1 mRNA, which is subsequently recognized by the YTHDC1 at a specific site in the 3'-UTR-3. This mechanism synergistically enhances FOXO1 expression and blocks autophagic flux leading to apoptosis in endothelial cells. In vivo, endothelial-specific METTL3 knockout attenuated aortic plaque formation in diabetic atherosclerotic mice and reduced FOXO1 expression along with autophagic apoptosis related proteins.</p><p><strong>Conclusions: </strong>The METTL3/YTHDC1 axis-mediated m⁶A modification of Foxo1 mRNA promotes endothelial autophagic apoptosis in diabetic atherosclerosis, revealing a promising therapeutic target.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376515","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":"Cardiac extracellular vesicle proteomics identifies mitochondrial and contractile dysfunction in carbon monoxide poisoning and their reversal by hyperbaric oxygen therapy.","authors":"Chien-Wei Hsiung, Yu-Chang Liu, Tzu-Hao Chen, Wei-Ting Chang, Ching-Ping Chang, Chien-Cheng Huang, Pao-Chi Liao","doi":"10.1186/s10020-026-01534-0","DOIUrl":"10.1186/s10020-026-01534-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Carbon monoxide poisoning (COP) induces systemic hypoxia and oxidative stress-related injury, leading to myocardial injury and persistent cardiac dysfunction. However, reliable biomarkers for monitoring long-term cardiac sequelae and therapeutic responses remain lacking. Extracellular vesicles (EVs), which reflect the molecular status of their cells of origin, may serve as candidate biomarkers for organ-specific injury. This study investigated whether cardiac EV proteins capture COP-induced myocardial and mitochondrial dysfunction and reflect the therapeutic effects of hyperbaric oxygen (HBO) therapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A rat model of COP was established with or without HBO treatment. Cardiac function was assessed by echocardiography, and myocardial injury was evaluated using histological, ultrastructural, and biochemical analyses. Cardiac-enriched EVs isolated from ex vivo whole-heart perfusate were used for global proteomic profiling. Candidate differentially abundant proteins were analyzed with emphasis on pathways related to mitochondrial dynamics, mitochondrial energy metabolism, calcium handling, and myocardial contractility. Key EV-associated and tissue proteins were further validated, and selected candidates were examined in serum-derived EVs as preliminary targeted circulating EV validation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;COP induced significant cardiac dysfunction, as evidenced by reduced ejection fraction and fractional shortening, together with histological myocardial injury, all of which were attenuated by HBO treatment. Proteomic analysis demonstrated that COP reshaped the cardiac EV proteome in a manner consistent with mitochondrial abnormalities, altered calcium-handling protein profiles, and impaired myocardial contractile function. These EV proteomic alterations were enriched in pathways related to mitochondrial dynamics, calcium signaling, and cardiac contractile regulation. Specifically, COP was associated with dysregulation of mitochondrial dynamics regulators, including optic atrophy type 1 (Opa1) and mitochondrial fission protein 1 (FIS1), as well as calcium-handling proteins such as ryanodine receptor 2 (Ryr2) and phospholamban (Pln). Ultrastructural and biochemical analyses showed mitochondrial cristae disruption, altered mitochondrial fusion-fission protein profiles, mitophagy-related protein changes, and pyroptosis-associated signaling in cardiac tissue following COP, whereas HBO mitigated these abnormalities. Notably, EV-associated Opa1 and FIS1 were associated with COP-related alterations in mitochondrial dynamic balance, whereas EV-associated Ryr2 and Pln were associated with impaired myocardial contractile parameters. Additional analysis of EV proteins related to mitochondrial function and ATP energy production further supported COP-associated mitochondrial energy metabolism-related protein remodeling. Targeted analysis of serum-derived EVs further showed that selected c","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376405","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":"Acute anti-obesity treatment with celastrol reduces body weight, cerebral inflammation and metabolic imbalances in mice.","authors":"Adriana Ferreiro, Maya Holgado, Raquel González-Alday, Sara González-Soto, Lidia M Fernandez-Sevilla, Ángeles Vicente, Pilar López-Larrubia, Blanca Lizarbe","doi":"10.1186/s10020-026-01530-4","DOIUrl":"10.1186/s10020-026-01530-4","url":null,"abstract":"<p><strong>Background: </strong>The global rise in obesity is predominantly driven by energy dense foods consumption and sedentary lifestyles that contribute to a growing burden of metabolic and neuroinflammatory comorbidities. Obesity is linked to a chronic low-grade inflammatory profile, as well as to a localized neuroendocrine imbalance and inflammatory response in the brain, including regions regulating energy homeostasis, reward and motivational centers. Anti-obesity medications that reduce body weight are being extensively used across the world, and the specific cerebral mechanisms underlying its action are yet to be clarified.</p><p><strong>Methods: </strong>We investigated the cerebral and systemic effects inherent to obesity development and treatment with celastrol, an anti-obesity and anti-inflammatory agent, in a murine model of diet-induced obesity (DIO) using a multimodal approach. We characterized obesity progression and celastrol acute treatment by comparing body weight (BW), food intake, changes in brain microstructure by in vivo magnetic resonance imaging (MRI) and ex vivo by immunofluorescence (IF), investigated its metabolic rearrangements using ¹H high-resolution magic angle spinning spectroscopy and draw the hormonal profiles between DIO and control animals, with or without treatment.</p><p><strong>Results: </strong>Our findings indicate that obesity induces detectable neuroinflammation, evident through diffusion MRI alterations and increased glial activation, with quantifiable morphological changes. Treatment resulted in significant BW reduction, diffusion MRI signal changes, particularly in the hypothalamus, a decrease in glial activation, a regularization of cerebral osmolyte concentrations, decreased cellular proliferation and astrocytic metabolism markers, and anti-inflammatory cytokine changes.</p><p><strong>Conclusions: </strong>These results support the role of celastrol as an anti-obesity treatment, with anti-inflammatory effects in the hypothalamus and associated cerebral metabolic rearrangements, and prove MRI techniques as valid tools to characterize its effects.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361573","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":"Integrative machine learning and CRISPR/Cas9 analysis reveals the role of APOE in lipid metabolism-associated kidney fibrosis.","authors":"Seyed Amirhossein Fazeli, Amir-Reza Javanmard","doi":"10.1186/s10020-026-01550-0","DOIUrl":"10.1186/s10020-026-01550-0","url":null,"abstract":"<p><p>Kidney fibrosis, characterized by excessive extracellular matrix deposition and progressive renal tissue remodeling, frequently culminates in End-stage kidney disease (ESKD). Emerging evidence links dysregulated lipid metabolism to renal fibrogenesis; however, the precise molecular mechanisms connecting these processes remain elusive. Apolipoprotein E (APOE), a central coordinator of lipid transport and metabolic homeostasis, is implicated in various metabolic and inflammatory diseases, yet its specific contribution to renal fibrotic signaling is poorly defined. In this study, we utilized an integrative framework comprising machine learning-assisted transcriptomic analysis, clinical validation, and CRISPR/Cas9 gene editing to elucidate the role of APOE in kidney fibrosis. Machine learning analysis of public transcriptomic datasets pinpointed APOE as a top-ranked gene highly correlated with renal fibrotic signatures and metabolic pathways. Consistently, APOE expression was significantly altered in clinical blood samples from Maintenance hemodialysis patients compared to healthy controls. To mechanistically validate these findings, we generated an in vitro APOE-knockout model using CRISPR/Cas9, followed by Angiotensin II stimulation to induce renal fibrogenesis. APOE ablation profoundly impacted the expression of canonical pro-fibrotic markers (COL1A1, FN1, and α-SMA) alongside crucial lipid metabolism genes (FASN and ACC), as confirmed by quantitative real-time PCR and Western blot analyses. Pathway enrichment further corroborated APOE's role as a critical regulatory node bridging lipid homeostasis and fibrotic cascades in the kidney. Overall, our findings establish APOE as a pivotal regulator of renal fibrotic remodeling, highlighting a direct mechanistic interplay between lipid metabolism and kidney fibrosis. Consequently, therapeutic modulation of APOE-dependent pathways may offer a promising strategy for treating chronic kidney disease and associated fibrotic pathologies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361681","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":"Targeting the crosstalk between Alzheimer's disease and gastrointestinal cancers.","authors":"Rui Gong, Hao Wang, Lei Cao, Haijing Niu, Axel Rominger, Zhongguang Luo, Ruiqing Ni","doi":"10.1186/s10020-026-01545-x","DOIUrl":"10.1186/s10020-026-01545-x","url":null,"abstract":"<p><p>Epidemiological studies have revealed an inverse association between Alzheimer's disease and cancer. Here, we discuss the mechanisms involved in the relationship between Alzheimer's disease and gastrointestinal cancers, particularly pancreatic and gastric-colorectal cancers. The gut‒brain axis and pancreas‒brain axis connect the central nervous system with peripheral organs and form immune‒metabolic networks. We focus on bidirectional tumor-brain communication, involving cell-death pathways, apoptosis, metabolic dysregulation, microbiota, metabolic dysregulation, neuroinflammation, immune system and sensory-sympathetic circuits, and neural remodeling. Furthermore, we discuss potential integrated, multitarget therapeutic strategies, including metabolic regulation, microbiome interventions, and immune modulation. Prospective longitudinal cohorts incorporating prediagnostic exposures and molecular pathology are needed to establish temporality.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352484","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":"Neuroprotective potential of a TrkB-FL-derived cell-penetrating peptide in cochlear synaptopathy and noise-induced hearing loss.","authors":"Elena Torres-Campos, Isabel Varela-Nieto, Margarita Díaz-Guerra","doi":"10.1186/s10020-026-01539-9","DOIUrl":"10.1186/s10020-026-01539-9","url":null,"abstract":"<p><strong>Background: </strong>Noise-induced hearing loss (NIHL) is the second leading cause of deafness globally. However, effective pharmacological treatments remain unavailable. Excitotoxicity, an early NIHL event, is a central mechanism in degeneration of cochlear synapses established between inner hair cells (IHCs) and spiral ganglion neurons (SGNs). This excitotoxic damage can trigger the degradation of the neurotrophic TrkB receptor, thereby inhibiting brain-derived neurotrophic factor (BDNF) signaling and challenging neurotrophin-based therapies for hearing loss.</p><p><strong>Methods: </strong>We employed an ex vivo model of excitotoxicity, where excitotoxicity was induced in cochlear explants by overstimulation of excitatory glutamate receptors, and an in vivo model of noise overexposure. The effects of excitotoxicity on the neurotrophic system and cell architecture were established by immunohistochemistry. Hearing function was evaluated in vivo by the auditory brainstem responses (ABR) test, performed before and after noise overexposure.</p><p><strong>Results: </strong>In this study, we evaluated the therapeutic potential in the inner ear of MTFL₄₅₇, a cell-penetrating peptide designed to prevent TrkB-FL degradation in brain excitotoxicity. MTFL₄₅₇ showed efficient distribution across cochlear cell types in both ex vivo and in vivo models, supporting its ability to reach the inner ear and suggesting that it can cross the blood-labyrinth barrier after systemic administration. In explants undergoing excitotoxicity, MTFL₄₅₇ prevented TrkB-FL dysregulation, partially restored downstream prosurvival signaling, and significantly reduced neuronal damage and features associated with cochlear synaptopathy. In vivo, despite known sex-dependent differences in susceptibility to noise-induced damage, treatment with MTFL₄₅₇ preserved auditory function and synaptic integrity in both males and females, although the magnitude of protection varied between sexes. Together, these findings support a protective effect of MTFL₄₅₇ in models of excitotoxic cochlear injury.</p><p><strong>Conclusions: </strong>These results support the therapeutic potential of peptide MTFL₄₅₇ for treatment of NIHL and possibly other types of sensorineural hearing loss likewise associated with excitotoxicity.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345784","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":"Inferring genetic associations of programmed cell death genes with retinitis pigmentosa through multimodal Mendelian randomization.","authors":"Nan Guo, Guang-Hua Peng","doi":"10.1186/s10020-026-01547-9","DOIUrl":"10.1186/s10020-026-01547-9","url":null,"abstract":"<p><strong>Background: </strong>Retinitis pigmentosa (RP), a leading cause of inherited blindness, lacks effective treatment, necessitating the elucidation of its pathogenesis and identification of novel therapeutic targets. This study aimed to identify the genetic role of programmed cell death (PCD)-related genes in RP pathogenesis via an integrative multimodal framework.</p><p><strong>Methods: </strong>We integrated summary-level data from genome-wide association studies (GWAS), expression/protein quantitative trait loci (eQTL/pQTL), and processed transcriptomic datasets. The workflow encompassed causal inference mainly using two-sample Mendelian randomization (MR), with complementary validation by summary-data-based MR (SMR); specificity validation via Bayesian colocalization, multivariable MR (MVMR), phenome-wide association study (PheWAS), and MR examining tissue specificity using GTEx eQTL data; and functional annotation through bulk and single-cell RNA-seq analyses. The study used publicly available genetic and transcriptomic databases. Primary analyses used GWAS summary statistics for RP (ebi-a-GCST90018912, ebi-a-GCST90013904, and ebi-a-GCST90013954). Validation was performed in bulk (GSE62020) and single-cell (GSE183206) retinal transcriptomic datasets. Exposures were genetically instrumented expression (cis-eQTL) or protein abundance (cis-pQTL) of PCD-related genes. Primary outcome was RP. Secondary outcomes included gene expression dysregulation, functional enrichment, immune cell infiltration, and cell-type-specific expression.</p><p><strong>Results: </strong>Integrative two-sample and SMR analyses identified eight core PCD-related genes with robust genetic evidence linking to RP (e.g., AIM2, odds ratio = 2.90, 95% confidence interval: 1.81-4.63), which showed consistent effects across multiple tissues and remained nominally significant in MVMR models adjusting for proxy phenotypes of smoking and physical activity (nominal P < 0.05). PheWAS showed no evidence of pleiotropy for these associations (all P > 5 × 10⁻⁸). In retinal transcriptomes, these genes were dysregulated and enriched in immune pathways; CIBERSORT analysis revealed correlated immune cell infiltration, including a strong negative correlation between H13 and M1 macrophages (r = -0.625, P < 0.05). Single‑cell RNA‑seq further pinpointed Müller glia as the most reprogrammed population (area under the curve score: 0.07).</p><p><strong>Conclusions: </strong>This multimodal study provides genetic evidence linking a core set of PCD-related genes to RP pathogenesis. The findings suggest a mechanistic model wherein dysregulation of these genes may contribute to immune dyshomeostasis and Müller glia dysfunction, emphasizing a network of promising therapeutic targets for this blinding disorder.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339296","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":"Immunogenic implications of translational readthrough modulate the association of F8 nonsense mutations with inhibitors in Hemophilia A.","authors":"Maria Francesca Testa, Mirko Pinotti, Alessio Branchini, Maria Elisa Mancuso, Francesco Bernardi, Dario Balestra","doi":"10.1186/s10020-026-01536-y","DOIUrl":"10.1186/s10020-026-01536-y","url":null,"abstract":"<p><strong>Background: </strong>Among F8 mutation types, main determinants of inhibitor development after replacement therapy in Hemophilia A (HA), nonsense mutations display wide variation in the associated risk. Translational readthrough (Rdthr) at premature termination codons (PTCs) produces traces of full-length factor VIII (FVIII) including missense and wild-type molecules (WT Rdthr), and may influence the immune response involved in inhibitor formation.</p><p><strong>Methods: </strong>For inhibitor association analysis, we investigated F8 genotypes, inhibitor status and Rdthr features in 335 PTCs (1048 patients), recorded in the European Association for Haemophilia and Allied Disorders (EAHAD) database, and exploited expression of F8 PTCs variants. Mean-differences in affinity of HLA-DR alleles for FVIII WT peptides and their missense counterparts were bioinformatically calculated.</p><p><strong>Results: </strong>WT Rdthr was higher for patients affected by PTCs not associated with inhibitor and was not predicted at all in patients with PTCs detected in at least three inhibitor positive cases (n = 136, p = 0.0001). WT Rdthr was lower for PTCs in the inhibitor prone FVIII light chain. Among FVIII PTCs fused with luciferase, quantitative output of WT Rdthr negative and positive groups did not differ, potentially highlighting for the positive group the importance of WT Rdthr to decrease inhibitor association. Readthrough output was the lowest among WT Rdthr negative PTCs, highly associated with inhibitors. The WT Rdthr prediction was extended to all PTCs that could arise by single nucleotide variations for the entire F8 coding sequence. Estimated WT Rdthr was higher in PTCs reported in EAHAD than those predicted (n = 662), foreseeing a higher risk of developing inhibitors. In silico mean differences in affinity of HLA-DR alleles for WT FVIII peptides and their missense counterparts, potentially arising from Rdthr of PTCs without WT formation (n = 297), were higher for missense variants predicted in patients with inhibitors than without (p < 0.0001), and increased for PTCs present in more than one patient with inhibitor, potentially supporting immunogenic features.</p><p><strong>Conclusions: </strong>The new genetic classification of HA PTCs may improve our knowledge about their relationship with inhibitors. It deserves to be explored for estimating inhibitor PTC association in HLA genotyped patients as well as in other human diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352495","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":"Prevalence of heterozygous and homozygous 9p21 deletions in human cancer: a tissue microarray study on 4,999 tumors from 125 different tumor types.","authors":"Natalia Gorbokon, Katharina Teljuk, Nina Schraps, Maximilian Lennartz, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Florian Viehweger, Florian Lutz, Christoph Fraune, Andreas M Luebke, Anne Menz, Ria Schlichter, Till Krech, Andrea Hinsch, Eike Burandt, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H Marx, Patrick Lebok, David Dum, Sarah Minner, Frank Jacobsen, Till S Clauditz, Thilo Hackert, Faik G Uzunoglu, Christian Bernreuther, Martina Kluth","doi":"10.1186/s10020-026-01542-0","DOIUrl":"10.1186/s10020-026-01542-0","url":null,"abstract":"<p><strong>Background: </strong>Homozygous 9p21 deletions are the major cause for MTAP deficiency, making cancer cells more vulnerable towards drugs targeting various pathways. This study aimed to assess the prevalence of heterozygous and homozygous 9p21 deletions in cancer.</p><p><strong>Methods: </strong>A tissue microarray containing 7,172 samples from 125 different tumor entities was analyzed by fluorescence in situ hybridization. This method allows the detection of deletions within single tumor cells, while admixted non-neoplastic cells are omitted. Consecutive sections were immunostained for MTAP and p16 (CDKN2A).</p><p><strong>Results: </strong>Among 4,999 evaluable tumors, 10.7% had heterozygous and 7.4% homozygous deletions, which occurred in different tumor categories. Homozygous deletions were most frequent in mesothelioma (up to 47.8%), pancreatic ductal adenocarcinoma (44.7%), and urothelial carcinoma (up to 36.4%) while heterozygous deletions predominated in squamous cell carcinoma (up to 34.3%), leiomyosarcoma (31.4%), and esophageal adenocarcinoma (30.8%). The proportion of homozygous 9p21 deletions was high in mesothelioma (up to 91.6%), urothelial carcinoma (up to 80.0%), and pancreatic ductal adenocarcinoma (76.4%), intermediate in squamous cell carcinomas of different organs (12.5-50.0%) and pulmonary adenocarcinoma (46.3%), and low in endometrioid (9.1%) and high-grade serous (4.0%) ovarian carcinoma. MTAP and p16 immunostaining was absent in homozygous 9p21 deletions, while heterozygously deleted cancers showed markedly decreased MTAP immunostaining (p < 0.0001), with unchanged p16 staining.</p><p><strong>Conclusions: </strong>These data provide a comprehensive overview on the prevalence on homozygous and heterozygous 9p21 deletions in cancer and demonstrate that different cancer types markedly differ in their ratio of homozygous/heterozygous 9p21 deletions. The strong concordance between homozygous 9p21 deletions and absent MTAP immunostaining highlights the effectiveness of immunohistochemistry in detecting MTAP deficiency.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13312514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352119","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":"Targeting Cathepsin B with p-coumaric acid rescues WWP1-dependent proteasomal degradation of NLRP3 in hyperuricemic nephropathy.","authors":"Fengqin Li, Yanzhe Wang, Xia Liu, Yue Wu, Naijun Miao, Jialing Wang, Xinyue Chen, Tong Wu, Qiao Fu, Chuchu Zeng, Nan Zhang, Xinmiao Xie, Xiaoxia Wang","doi":"10.1186/s10020-026-01544-y","DOIUrl":"10.1186/s10020-026-01544-y","url":null,"abstract":"<p><strong>Background: </strong>Hyperuricemic nephropathy (HN) is a prevalent metabolic disorder characterized by tubulointerstitial inflammation and fibrosis, driven primarily by aberrant NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. However, effective therapies targeting this pathogenic axis remain elusive. We aimed to identify a pharmacological intervention for HN and elucidate its mechanisms.</p><p><strong>Methods: </strong>A targeted phenotypic screen of natural phenolic compounds was conducted against uric acid (UA)-induced inflammasome responses. Multi-omics profiling, molecular docking, and multi-dimensional biophysical assays-including surface plasmon resonance, cellular thermal shift assays, and circular dichroism-and site-directed mutagenesis were utilized to identify and characterize the direct molecular target. The underlying post-translational regulatory mechanism was investigated through co-immunoprecipitation and ubiquitination assays. In vivo efficacy and short-term tolerability were evaluated in a rat model of HN. Clinical relevance was assessed via renal biopsies and clinical sample analysis.</p><p><strong>Results: </strong>We identified p-coumaric acid (p-CA) as a potent pharmacological candidate. Mechanistically, p-CA engages the Cathepsin B (CTSB) active-site/occluding-loop region, involving residues Cys26 and His110, and suppresses CTSB enzymatic activity. Notably, we uncovered a post-lysosomal regulatory model in which UA-induced lysosomal CTSB leakage is associated with a CTSB activity-associated reduction in WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) protein abundance/stability, thereby impairing WWP1-dependent K48-linked polyubiquitination and proteasomal clearance of NLRP3 and promoting inflammasome activation. p-CA-mediated CTSB inhibition preserves WWP1 protein abundance, restores NLRP3 proteasomal clearance, and attenuates downstream pyroptosis, inflammation, and fibrogenesis. CTSB knockdown attenuated the additional protective effect of p-CA, while pharmacological CTSB inhibition phenocopied p-CA, supporting CTSB pathway dependence. Furthermore, in vivo evaluations demonstrated that p-CA exerts urate-independent renoprotection without overt short-term systemic toxicities associated with synthetic CTSB inhibitors. Clinically, aberrant CTSB and NLRP3 upregulation correlated with impaired renal function in patients from the hyperuricemia-associated CKD cohort.</p><p><strong>Conclusions: </strong>Our findings support the CTSB-WWP1-NLRP3 regulatory axis as a previously unrecognized pathogenic mechanism of HN, revealing how lysosomal damage drives inflammasome hyperactivation by disrupting ubiquitin-dependent clearance. The precise molecular mechanism linking CTSB activity to WWP1 turnover remains to be fully defined. Targeting CTSB with p-CA provides a promising prophylactic or co-treatment candidate for HN warranting further translational evaluation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339389","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}