Molecular Medicine最新文献

{"title":"A multiomic investigation of human milk-derived extracellular vesicles in perinatal HIV and antiretroviral therapy exposure.","authors":"Allison Kupsco, Jennifer Jao, Landon Myer, Elaine J Abrams, Fang Wang, Jalean Dominguez, Allison Zerbe, Elton Mukonda, Hlengiwe P Madlala, Sandisiwe Matyesini, Daniel T Robinson, Yunping Qiu, Irwin J Kurland, Haotian Wu","doi":"10.1186/s10020-026-01567-5","DOIUrl":"10.1186/s10020-026-01567-5","url":null,"abstract":"<p><strong>Background: </strong>Human milk (HM) is beneficial for early infant development, and breastfeeding is recommended globally for women with HIV (WHIV) on antiretroviral therapy (ART). HM has a high extracellular vesicle (EV) content, and distinct HM fractions may be enriched for unique small metabolites, lipids, oxylipins, and microRNAs, which may differ by HIV/ART exposure. Our objective was to characterize the metabolomic and miRNA differences between milk fractions and in relation to HIV/ART.</p><p><strong>Methods: </strong>HM was collected at 6 weeks postpartum from WHIV receiving ART and HIV-seronegative women in South Africa (N = 20/group). Milk was fractionated into whole milk, skim milk, and EVs, which we isolated from skim milk using size-exclusion chromatography. Widely targeted small metabolite (~ 550 metabolites) and lipid profiling (~ 1500 lipid species in 24 + lipid classes) were measured with Ultra Performance Liquid Chromatography-Triple quadrapole Mass Spectrometry on whole milk, skim milk, and EVs. EV-miRNAs were sequenced on an Illumina NovaSeq. We used linear models to compare levels of lipids, metabolites, and miRNAs in HM EVs of WHIV versus HIV-seronegative women adjusting for covariates.</p><p><strong>Results: </strong>There were 658 lipids, 130 oxylipins, and 274 small metabolites detected across all HM fractions, with fewer compounds detected in HM EVs compared to whole and skim milk. HM EVs were enriched for fatty acid metabolism and metabolic products of linoleic acid (false discovery rate [FDR] p < 0.05). Triacylglycerols, TAG47:0 and TAG49:0, were lower in whole and skim milk of WHIV participants. Conversely, 18 small metabolites in HM EVs were associated with HIV status, but not in whole or skim milk. Of 187 detected EV-miRNAs, miR-148b-5p was significantly lower in WHIV, which was also validated by qPCR.</p><p><strong>Conclusions: </strong>These preliminary results suggest that EVs may better represent differences in milk metabolites from HIV/ART exposure than whole milk or skim milk. EV contents altered in WHIV may be relevant for lipid, vitamin and energy metabolism, and metabolic health. Future research is warranted to assess the relationship between HM EV contents and child health.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov-ID: NCT04991402.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471900","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":"Role of chromatin remodeling and immunopharmacology in cancer therapy.","authors":"Syeda Kiran Riaz, Mehwish Iqbal, Farwa Tahir, Tariq Iqbal, Faraz Ahmad, Muhammad Saboor, Asif Naseer, Shafiul Haque, Vaibhav Srivastava","doi":"10.1186/s10020-026-01557-7","DOIUrl":"10.1186/s10020-026-01557-7","url":null,"abstract":"<p><p>Epigenetic modifications play a crucial role in cancer, influencing cellular physiology, extracellular matrix (ECM) remodeling, and immune responses. With growing emphasis on chromatin remodeling and the epigenetic regulation of immunity, these regulatory pathways and related players have become focal points of oncological investigations. Epigenetic manipulation of immune system components has emerged as a promising strategy in cancer treatment. Several FDA-approved \"epi-drugs\" target the epigenome to modulate immune responses and offer new opportunities across different cancers. DNA repair pathways contribute significantly to the avoidance of cancer initiation and also contribute to cellular resistance in cancer treatment. Chromatin remodelers such as INO80, Fun30, and RAD54 play essential roles in DNA damage response (DDR) through homologous recombination and non-homologous end-joining pathways, and their dysregulation leads to genome instability and tumor progression. Chromatin remodeling complexes, including SWI/SNF and CHD families, are frequently altered across various cancer types, further highlighting their role in cancer pathophysiology. Targeting these chromatin modifiers and associated DNA repair mechanisms may provide novel therapeutic options. In addition, combining epigenetic modulators with immunotherapies has shown promise in enhancing responses to immune checkpoint blockade. Epigenetic drugs such as histone deacetylase (HDAC) inhibitors and DNA methylation inhibitors are being explored for their synergistic effects with immunotherapy. While the interplay between chromatin remodeling, DNA repair, and immune responses provides a strong framework for developing targeted oncological strategies, further research is required to better understand these interactions and optimize their clinical application.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456511","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":"Glycosylation modification: a trigger for obesity and its complications?","authors":"Changzan Wang, Wenying Yi, Xianghui Li, Xinyu Li, Meiying Wu, Wen Zhou, Maierhaba Maimaitiaili, Dilare Tuerhong, Nuerbiye Nuermaimaiti","doi":"10.1186/s10020-026-01565-7","DOIUrl":"10.1186/s10020-026-01565-7","url":null,"abstract":"<p><p>Obesity and its related metabolic diseases have increasingly become a significant public health challenge threatening the health of populations worldwide. The pathophysiological mechanisms contributing to the progression of obesity are intricate and diverse, highlighting the need for the creation of novel and effective intervention strategies aimed at the treatment of obesity and its associated metabolic diseases. An increasing number of studies indicate that glycosylation modifications play a crucial role in the onset and progression of obesity and its complications. Studies on glycosylation not only reveal its involvement in regulating the mechanisms of obesity and its complications but also provide new avenues for targeted therapies. Although significant advancements have been made in understanding the fundamental molecular mechanisms by which glycosylation modifications affect obesity and its related complications, many questions remain unanswered. For instance, through which specific sites does glycosylation regulate the occurrence of obesity and its complications? Furthermore, do glycosylation modifications interact with other post-translational modifications (PTMs) of proteins in the regulation of obesity and its complications? What are the specific pathways of O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in obesity and its complications? This article summarizes recent research on the role of glycosylation in obesity and its complications, lists relevant specific glycosylation sites, and discusses the interactions between glycosylation modifications and other PTMs of proteins, providing new perspectives and insights for clinical treatment of obesity and its complications.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471906","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":"Single-cell transcriptomic profiling reveals PDK4 upregulation and impaired VEGF-C/VEGFR3 signaling in cardiac lymphatic endothelial cells in diabetic cardiomyopathy.","authors":"Yufeng Yan, Xunuo Wang, Congfei Zhu, Zihao Jiang, Jing Wang, Junjie He, Lei Xu, Xiaobin Zhou, Qing Ge, Zuoying Hu, Guangfeng Zuo","doi":"10.1186/s10020-026-01571-9","DOIUrl":"10.1186/s10020-026-01571-9","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cardiomyopathy (DCM) is characterized by microvascular dysfunction. While vascular endothelial cells (ECs) have been widely studied, the role of cardiac lymphatic ECs (LECs) in DCM remains unknown.</p><p><strong>Methods: </strong>A mouse model of DCM was induced by a high-fat diet (HFD) with streptozotocin (STZ) injection. We performed single-cell RNA sequencing (scRNA-seq) on cardiac tissues from mice with DCM and control mice. We then applied clustering, RNA velocity, pseudotime analysis, and CellChat cell-cell communication analysis to define lymphatic endothelial cell (LEC) heterogeneity and underlying regulatory networks.</p><p><strong>Results: </strong>Our analysis revealed profound pathological remodeling of the cardiac lymphatic architecture in diabetic hearts, marked by decreased LEC numbers and impaired function. Cell-cell communication analysis demonstrated impaired VEGF-C/VEGFR3 signaling between venous ECs (VECs) and LECs in diabetic hearts. We identified the upregulation of pyruvate dehydrogenase kinase 4 (PDK4) expression in diabetic LECs as a key driver of metabolic reprogramming, leading to impaired cell migration.</p><p><strong>Conclusions: </strong>This study mapped the profile of LECs in diabetic hearts and revealed a dual pathogenic mechanism involving metabolic disorders driven by PDK4 and disruption of venous-lymphatic communication. These findings may provide new strategies for the treatment of DCM.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456454","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":"CCR2-dependent monocytes gut-homing contributes to enteric neuroplastic changes in a mouse model of diet-induced obesity.","authors":"Clarissa Pierucci, Sofia Faggin, Laura Benvenuti, Valentina Caputi, Chiara Ippolito, Cristina Segnani, Vanessa D'Antongiovanni, Giulia Valdiserra, Lorenzo Flori, Rocchina Colucci, Maria Cecilia Giron, Luca Antonioli, Nunzia Bernardini, Carolina Pellegrini","doi":"10.1186/s10020-026-01560-y","DOIUrl":"10.1186/s10020-026-01560-y","url":null,"abstract":"<p><strong>Background: </strong>Enteric inflammation and immune cell activation promote enteric neuroplastic changes and CCR2-dependent monocyte recruitment, contributing to obesity-associated colonic dysmotility and chronic inflammation. Here, we examined the role of C-C motif chemokine ligand (CCL2)/C-C chemokine receptor 2 (CCR2)-mediated blood monocytes gut-homing in colonic motor dysfunctions in mice with high fat diet (HFD)-induced obesity.</p><p><strong>Methods: </strong>Wild-type C57BL/6J mice were fed HFD or standard diet (SD) for 8 weeks. Subgroups received the CCR2 antagonist RS504393 (2 mg/kg/day, oral) or vehicle throughout the HFD intake. Body weight and body mass index (BMI) were monitored starting from HFD intake. Colonic transit was assessed by fecal pellet output. In vitro colonic contractility was evaluated by assessing substance P (SP)-induced contractile responses, along with analysis of SP-positive neurons. Immunohistochemistry was used to quantify CCR2⁺ monocytes and CD64⁺/Iba-1⁺ macrophages within the myenteric plexus. Colonic expression of CCL2 in enteric neurons (HuC/D⁺) and glial cells (GFAP⁺) was assessed. Gut vascular barrier integrity was evaluated via PV-1 expression and plasma lipopolysaccharide-binding protein (LBP) levels. The effects of CCR2 blockade on motility, neuronal SP expression, chemokine expression, and monocyte recruitment were analyzed.</p><p><strong>Results: </strong>HFD mice displayed an increase in body weight and BMI. An altered in vivo colonic transit along with an increased in vitro tachykininergic contractions and myenteric SP immunopositivity were detected in HFD mice. HFD mice exhibited marked infiltration of monocyte-derived macrophages (CD64⁺, Iba-1⁺) within the muscularis layer, in close spatial association with SP-positive nerve fibers and neuromuscular vasculature. Increased CCL2 expression was observed in both enteric neurons and glial cells, alongside evidence of compromised gut vascular barrier function. Pharmacological CCR2 inhibition attenuated weight gain and significantly improved colonic transit. Moreover, CCR2 blockade normalized tachykininergic hyperactivity, reduced SP expression, decreased colonic CCL2 levels, and limited monocyte/macrophage accumulation in the enteric neuromuscular compartment.</p><p><strong>Conclusion: </strong>During obesity, the activation of the CCL2/CCR2 pathway promotes the recruitment of blood-derived monocytes to the gut, driving neuroimmune remodelling within the enteric nervous system. Blood monocyte-derived macrophages modulate tachykininergic pathways, contributing to colonic dysmotility. Targeting CCR2-dependent gut immune cell trafficking may represent a novel therapeutic strategy for obesity-associated GI dysfunction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456473","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":"ACL injury reprograms quadriceps myonuclear epigenetic and transcriptional signatures in mice.","authors":"Nicholas T Thomas, Camille R Brightwell, Thomas Carter, Alexander R Keeble, Sara Gonzalez-Velez, Christine M Latham, Allison M Owen, Yuan Wen, Kevin A Murach, Christopher S Fry","doi":"10.1186/s10020-026-01568-4","DOIUrl":"10.1186/s10020-026-01568-4","url":null,"abstract":"<p><strong>Background: </strong>ACL injury is a debilitating sport-related injury that induces prolonged deficits in muscle size and strength. Using a time-course of in vivo fluorescent metabolic labeling of nascent RNA in an ACL injury mouse model, we identified upregulated myonuclear transcriptional output early following the injury.</p><p><strong>Methods: </strong>To define altered myonuclear transcription, we bred HSA^rtTA/rtTA:TetO-H2B-GFP mice to allow for stable in vivo fluorescent labeling and sorting of resident (non-satellite cell-derived) myonuclei 3-days post ACL transection surgery. We performed myonucleus-specific RNA sequencing (RNAseq) and reduced representation bisulfite sequencing (RRBS) to capture altered myonuclear transcriptional and epigenetic signatures following ACL injury.</p><p><strong>Results: </strong>Integration of these datasets revealed transcriptional reprogramming of quadriceps myonuclei following ACL injury toward upregulation of fibrosis related genes and downregulation of metabolism related genes. When integrating bulk tissue RRBS with bulk tissue RNAseq, we demonstrate a similar, but more robust pattern of transcriptional reprogramming, suggesting the altered epigenetic landscape following ACL injury extends beyond myonuclei.</p><p><strong>Conclusions: </strong>Our results support a model of epigenetically-encoded muscle maladaptation following orthopedic injury, with implications for understanding a \"muscle memory\" of persistent dysfunction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456491","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":"Integrated analysis of STRC variants in hereditary hearing impairment using maker-mediated refinement of long-read sequencing with MLPA validation.","authors":"Cheng-Yu Tsai, Yue-Sheng Lu, Yu-Ting Chiang, Ming-Yu Lo, Pei-Hsuan Lin, Shih-Feng Tsai, Chuan-Jen Hsu, Pei-Lung Chen, Jacob Shu-Jui Hsu, Chen-Chi Wu","doi":"10.1186/s10020-026-01553-x","DOIUrl":"10.1186/s10020-026-01553-x","url":null,"abstract":"<p><strong>Background: </strong>Sensorineural hearing impairment (SNHI) is a common disorder with a significant genetic basis. Standard next-generation sequencing (NGS) often fails to accurately identify pathogenic variants in the STRC gene due to its complex genomic structure, including large rearrangements and a highly homologous pseudogene. Long-read sequencing (LRS) offers improved resolution for these complex regions.</p><p><strong>Methods: </strong>We developed a comprehensive workflow that integrates PacBio-based LRS with marker-mediated refinements and MLPA validations to specifically address pseudogene interference. This methodology was applied to analyze the STRC gene in a cohort of 100 unrelated Taiwanese patients with SNHI of unknown genetic origin after initial NGS screening.</p><p><strong>Results: </strong>We identified bi-allelic STRC variants in 11 unrelated patients (11% diagnostic yield), including homozygous deletions, compound heterozygous deletions and conversions, and compound heterozygous single nucleotide variants (SNVs) and copy number variants (CNVs). All unrelated cases resolved with bi-allelic STRC variants were affected with mild or moderate SNHI, occupying 15.1% of total 73 mild-to-moderate SNHI patients in this study.</p><p><strong>Conclusion: </strong>Our results highlight the diagnostic utility of this combined strategy, integrating LRS with marker-mediated refinements that validated by MLPA assays, in detecting complex STRC variants and advance the understanding of the genetic etiology of SNHI that remains unresolved by conventional NGS approaches.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430783","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":"Bispecific antibody AP402 targets p95HER2 and induces costimulation through CD137 to improve efficacy for HER2-positive tumors.","authors":"Po-Lin Huang, Hsin-Ta Hsieh, Hung-Tsai Kan, Ching-Hsuan Hsu, Kuan-Ming Huang, Hsin-Yu Chen, Tzu-Ning Chen, Jhong-Jhe You","doi":"10.1186/s10020-026-01564-8","DOIUrl":"10.1186/s10020-026-01564-8","url":null,"abstract":"<p><strong>Background: </strong>Outcomes for HER2-positive cancers have been greatly improved by trastuzumab and other HER2-targeted therapies. However, many tumors express a truncated p95HER2 variant that lacks the extracellular trastuzumab binding site. Since these tumors exhibit resistance and more aggressive disease phenotypes, the AP402 bispecific antibody was developed to target p95HER2 and engage activated T cells toward tumor cells via CD137 engagement.</p><p><strong>Methods: </strong>AP402 was characterized in terms of binding, anti-tumor activity and safety using in vitro and in vivo models. Using p95HER2- and full-length HER2-expressing tumor cells, antibody-dependent cellular cytotoxicity (ADCC) assays were performed. AP402-mediated T cell activation was evaluated by measuring IFN-γ production. In vivo anti-tumor efficacy was tested in humanized p95HER2-transgenic tumor models and patient-derived xenograft (PDX) models. The safety profile was assessed with cytokine release assays and a toxicology study in cynomolgus monkeys.</p><p><strong>Results: </strong>AP402 induced ADCC in p95HER2-expressing tumor cells and also showed activity against full-length HER2-positive cells. In addition, the CD137-binding arm robustly activated T cells in a p95HER2-binding-dependent manner. In humanized p95HER2-transgenic breast and lung tumor mouse models and in PDX models of p95HER2-positive breast cancer, AP402 significantly reduced tumor weights and volumes. Cytokine release assays and in vivo toxicology studies suggested the molecule has low risk of adverse effects.</p><p><strong>Conclusion: </strong>AP402 is a promising therapeutic agent for p95HER2-positive cancers with dual functions of targeting p95HER2 and enhancing p95HER2-dependent T cell activation. These functions may overcome resistance to current HER2-targeted therapies, and the favorable safety profile of AP402 suggests excellent potential for clinical application.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148437184","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":"Hydrogen alleviates sepsis-associated encephalopathy via ATG9B-dependent mitophagy.","authors":"Xiaoli Yu, Xiaofan Huang, Yu Song, Jianfeng Liu, Fei Huang, Jiatian Cui, Keliang Xie, Yan Cui","doi":"10.1186/s10020-026-01566-6","DOIUrl":"10.1186/s10020-026-01566-6","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-associated encephalopathy (SAE) is a severe complication with high mortality and limited therapeutic options. Molecular hydrogen (H₂) has shown neuroprotective potential, but its mechanism remains elusive.</p><p><strong>Methods: </strong>SAE was induced in C57BL/6J mice by cecal ligation and puncture, with or without 2% H₂ inhalation. HT22 hippocampal neurons were challenged with lipopolysaccharide in hydrogen-rich medium. H₂ intervention was administered via inhalation or hydrogen-rich medium. Cognitive function was evaluated by novel object recognition and Y-maze tests. Transcriptome sequencing was used to identify key signaling pathways regulated by H₂. The neuroprotective mechanism of H₂ was explored by assessing mitophagy, apoptosis, reactive oxygen species, and mitochondrial membrane potential. ATG9B was knocked down using siRNA in vitro and AAV-shRNA in the hippocampal CA1 region in vivo to clarify its function.</p><p><strong>Results: </strong>H₂ inhalation increased 7-day survival in CLP-induced septic mice from 40% to 75%, reduced systemic and hippocampal pro-inflammatory cytokines, and alleviated hippocampal neuronal damage and cognitive dysfunction. Transcriptomic profiling identified ATG9B as the most significantly upregulated mitophagy-related gene by H2. Mechanistically, H₂ upregulated ATG9B expression, which in turn enhanced PINK1-Parkin-mediated mitophagy flux, thereby coordinating mitophagosome formation and lysosomal fusion, leading to clearance of damaged mitochondria and reduced neuronal apoptosis. ATG9B knockdown completely abolished H₂-induced mitophagy flux, mitochondrial protection, and cognitive improvement.</p><p><strong>Conclusions: </strong>H₂ alleviates SAE by upregulating ATG9B and restoring PINK1-Parkin-dependent mitophagy. The ATG9B-mitophagy axis represents a novel therapeutic target, and H₂ inhalation emerges as a potential strategy for sepsis-associated cognitive impairment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422542","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":"PRMT5 promotes psoriatic inflammation through mediating dimethylation of p65 in keratinocytes.","authors":"Xiaoru Hu, Yuzi Tian, Qingyu Hong, Wanyao Liu, Weina Li, Jia Guo","doi":"10.1186/s10020-026-01558-6","DOIUrl":"10.1186/s10020-026-01558-6","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is a chronic inflammatory skin disease driven by aberrant keratinocyte activation and immune dysregulation. Protein arginine methyltransferase 5 (PRMT5) was identified as a candidate regulator in psoriatic keratinocytes, yet its function and mechanistic role in psoriasis pathogenesis remain unclear.</p><p><strong>Methods: </strong>We analyzed multiple public bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) transcriptomic datasets from psoriasis patients to assess PRMT5 mRNA expression and distribution. Protein expression was further validated by immunofluorescence staining of psoriatic lesion biopsies. Functional validation employed siRNA-mediated Prmt5 knockdown in imiquimod-induced psoriasis model. Transcriptomic profiling combined with in vitro human primary keratinocytes experiments was performed with PRMT5 knockdown or inhibition to map downstream potential mechanisms. Specific mechanistic investigations included co-immunoprecipitation, molecular docking, GST pull-down, mass spectrometry, and site-directed mutagenesis to characterize the PRMT5-p65 interaction and symmetric dimethylarginine (SDMA) modification. Finally, the therapeutic potential of PRMT5 inhibition by EPZ015666 was evaluated in imiquimod and IL-23-induced psoriasis models.</p><p><strong>Results: </strong>PRMT5 was markedly upregulated in psoriatic keratinocytes. Knockdown of Prmt5 reduces local inflammation responses in the imiquimod-induced mouse model. Transcriptomic profiling combined with in vitro detection defined that inhibition of PRMT5 can dampen the inflammatory response of keratinocytes. Mechanistically, PRMT5 inhibition markedly reduces p65 protein levels, prompting further exploration of the PRMT5-p65 axis. Co-immunoprecipitation, molecular docking and GST pull down assay confirmed a direct PRMT5-p65 interaction; PRMT5 knockdown attenuated this interaction, diminishes symmetric dimethylarginine (SDMA) modification of p65, and compromises p65 protein stability. Accordingly, p65 overexpression restored inflammatory cytokine production in PRMT5-knockdown keratinocytes, functionally validating this regulatory axis. Mass spectrometry combined with site-directed mutation experiments revealed that PRMT5 facilitates p65 symmetric dimethylation at R158 and R166, which suppresses autophagy-mediated lysosomal degradation, thereby promoting p65-dependent cytokines expression. Pharmacological inhibition of PRMT5 with EPZ015666 ameliorates psoriatic inflammatory responses in vivo, underscoring its translational potential value.</p><p><strong>Conclusions: </strong>These findings establish a PRMT5-p65 regulatory axis wherein PRMT5-mediated symmetric dimethylation at R158 and R166 stabilizes p65 by autophagy-mediated lysosomal degradation and amplifies NF-κB-driven inflammation in keratinocytes, identifying PRMT5 as a potential therapeutic target in psoriasis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422600","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}