Molecular Medicine最新文献

{"title":"WHAMM deficiency alters splenic B-cell populations, BCR signaling, and actin remodeling.","authors":"Nanshu Xiang, Ziyin Zhang, Yi Wang, Linhua Wang, Lu Yang, Xiaoyu Sun, Chaohong Liu","doi":"10.1186/s10020-026-01538-w","DOIUrl":"10.1186/s10020-026-01538-w","url":null,"abstract":"<p><p>Members of the Wiskott-Aldrich syndrome protein (WASP) family orchestrate cytoskeletal reorganization that modulates B-cell receptor (BCR) signaling and B-cell fate decisions. WHAMM, a WASP-family nucleation-promoting factor member that associates with actin, membranes and microtubules, has not been functionally characterized in B cells. To investigate the role of WHAMM in B-cell development and function, we analyzed a conditional mouse model in which Whamm was deleted in the B-cell lineage. WHAMM-deficient mice exhibited altered splenic B-cell composition, characterized by an accumulation of splenic transitional B cells and a reduction of follicular B cells. Meanwhile, WHAMM deficiency altered the spatial organization and kinetics of proximal BCR signaling, and modified the dynamics of BCR-induced actin remodeling. However, WHAMM-deficient B cells showed largely preserved BCR internalization, antigen presentation, PI3K-AKT-mTOR signaling, ROS production, and mitochondrial membrane potential. Together, this work indicates that WHAMM helps shape splenic B-cell populations and regulates proximal BCR signaling and actin dynamics, while several downstream functional responses remain largely preserved in this study.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865888","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":"Short-chain fatty acids as key mediators of the microbiota-gut-brain axis in chronic cerebral hypoperfusion: mechanisms and therapeutics.","authors":"Junchen Si, Peijian Wang, Zhongchen Li, Jiheng Hao, Jiyue Wang, Liyong Zhang","doi":"10.1186/s10020-026-01616-z","DOIUrl":"10.1186/s10020-026-01616-z","url":null,"abstract":"<p><p>Chronic cerebral hypoperfusion (CCH) is an important contributor to vascular cognitive impairment and neurodegenerative disorders, characterized by neuronal injury, blood-brain barrier (BBB) disruption, neuroinflammation, mitochondrial dysfunction, and synaptic impairment. Increasing evidence suggests that the microbiota-gut-brain axis plays a crucial role in ischemic brain injury. CCH is associated with gut microbiota dysbiosis, intestinal barrier dysfunction, and reduced production of microbiota-derived short-chain fatty acids (SCFAs), which may be linked to cognitive decline through bidirectional gut-brain communication. This review summarizes the mechanisms potentially involved in CCH-related neurological damage and highlights the potential neuroprotective effects of SCFAs, including regulation of neuroinflammation, BBB integrity, mitochondrial homeostasis, neuronal apoptosis, and synaptic plasticity. Furthermore, potential microbiota-targeted therapeutic strategies, such as fecal microbiota transplantation, probiotics/prebiotics, and SCFA supplementation, are discussed. Targeting gut microbiota-derived SCFAs may represents a promising approach for improving CCH-associated cognitive impairment, although further clinical validation is required.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062853","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":"NETs drive CD4⁺ T cell dysfunction in sepsis via mitochondrial ROS and impaired calcium signalling.","authors":"Hongru Li, Xuan Wang, Keran Sun, Jiachao Wang, Jiao Li, Enhao Zhang, Xiaoqing Li, Changwei Su, Zixin Li, Yushan Lin, Miao Li, Xiurong Wang, Hong Zhang, Chenhui Li, Lin Wei, Cuiqing Ma","doi":"10.1186/s10020-026-01607-0","DOIUrl":"10.1186/s10020-026-01607-0","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a life-threatening condition with high mortality, in which sepsis-induced immunosuppression-characterized by CD4⁺ T cell dysfunction and apoptosis-worsens clinical outcomes. The mechanistic link between neutrophil extracellular traps (NETs) and CD4⁺ T cell fate in sepsis remains poorly elucidated.</p><p><strong>Methods: </strong>We integrated plasma analysis from 50 sepsis patients and 31 healthy controls, a murine cecal ligation and puncture (CLP) sepsis model, and in vitro assays with Jurkat cells and primary CD4⁺ T cells. We investigated the effects of NETs on CD4⁺ T cell calcium signaling and mitochondrial function, and verified the therapeutic efficacy of DNase I combined with the mitochondrial-targeted antioxidant mitoTEMPO.</p><p><strong>Results: </strong>Circulating NETs were significantly elevated in sepsis patients, positively correlated with disease severity (SOFA score) and negatively correlated with peripheral CD4⁺ T cell counts. NETs disrupted intracellular calcium homeostasis by inhibiting store-operated calcium entry, suppressing calcineurin activity and NFAT nuclear translocation, thus impairing T cell activation and IL-2 production. Additionally, NETs induced mitochondrial dysfunction via excessive mitochondrial reactive oxygen species (mtROS) production and reduced mitochondrial calcium uptake, leading to loss of mitochondrial membrane potential, structural damage, and subsequent CD4⁺ T cell apoptosis. In CLP mice, monotherapy with either DNase I or mitoTEMPO partially attenuated CD4⁺ T cell injury, while the combination significantly improved 7-day survival compared with monotherapy or vehicle, reduced plasma organ injury markers, and alleviated splenic lymphocyte apoptosis.</p><p><strong>Conclusion: </strong>The NETs-mtROS axis represents an important pathway driving CD4⁺ T cell death in sepsis. Dual targeting of NETs and mitochondrial oxidative stress holds promising therapeutic potential for ameliorating sepsis-induced immunosuppression.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074806","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":"Label-free optical biomarker for prostate cancer diagnosis.","authors":"Shagufta Rehman Alam, Karsten Siller, Robert Dreicer, Ammasi Periasamy","doi":"10.1186/s10020-026-01605-2","DOIUrl":"10.1186/s10020-026-01605-2","url":null,"abstract":"<p><strong>Background: </strong>Reprogramming of cellular metabolism in cancer leads to changes in the activity of metabolic coenzymes NAD(P)H and FAD which can be used as markers of tumorigenesis and metastasis. NAD(P)H and FAD form coupled redox pair and regulator of mitochondrial energy metabolism. Since NAD(P)H and FAD are endogenous and auto fluorescent, the coupled redox pair can hence be exploited as a reporter for metabolic activity in tumor microenvironment.</p><p><strong>Methods: </strong>We have developed a 2P-FLIRR assay (2-photon Fluorescence Lifetime based Redox Ratio), a sensitive metabolic optical biomarker for tumor diagnosis in prostate cancer (PCa) patients' tissue sections. We have imaged and used our novel 2P-FLIRR metric which is the ratio of the enzyme-bound fractions of NAD(P)H and FAD to evaluate PCa patients' surgically resected tissue sections. These were PCa adenocarcinomas with different Gleason grades.</p><p><strong>Results: </strong>In comparison with conventional H&E histopathology, our 2P-FLIRR assay showed the potential to distinguish tumor-enriched regions from normal prostate tissue in unstained frozen patient tissue sections. Lower FLIRR values were observed to correspond to tumor versus higher FLIRR values to normal prostate.</p><p><strong>Conclusion: </strong>This pilot feasibility study demonstrates that 2P-FLIRR detects metabolic contrast between prostate cancer and normal prostate tissue in frozen human patient tissue sections. Our study identifies for the first time quantitative 2P-FLIRR as a potential sensitive diagnostic optical biomarker for PCa.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081618","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: Mechanistic insights into 5-aminolevulinic acid photodynamic therapy for acne vulgaris: targeting lipogenesis via the OLR1-Wnt/β-catenin pathway.","authors":"Jia Yan, Linglin Zhang, Qingyu Zeng, Yitao Qian, Ke Li, Xiaojing Liu, Yun Wu, Yu Yan, Haiyan Zhang, Szeman Cheung, Jia Liu, Ronald Sroka, Xiuli Wang, Lei Shi","doi":"10.1186/s10020-026-01602-5","DOIUrl":"10.1186/s10020-026-01602-5","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762346","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":"Elucidating the mechanism underlying incomplete immune recovery in people living with HIV through CD4⁺ and CD8⁺ T cell multi-omics.","authors":"Marina Flores-Piñas, Silvia Chafino, Consuelo Viladés, Pere Domingo, Beatriz Villar, Paula Prieto, Alexy Inciarte, Josep Mallolas, Julià Blanco, Eugènia Negredo, Jordi Navarro, Marcos Elizalde-Horcada, Verònica Alba, Anna Martí, Yolanda M Pacheco, Francesc Vidal, Joaquim Peraire, Anna Rull","doi":"10.1186/s10020-026-01575-5","DOIUrl":"10.1186/s10020-026-01575-5","url":null,"abstract":"<p><strong>Background: </strong>A subset of people living with HIV (PLHIV), known as immunological non-responders (INR), fails to achieve adequate CD4⁺ T cell recovery despite viral suppression with antiretroviral therapy (ART). These individuals face an increased risk of adverse clinical outcomes. This study aims to explore the intracellular mechanisms and molecular signatures underlying this incomplete immune recovery using a multi-omics approach.</p><p><strong>Methods: </strong>The study analysed CD4⁺ and CD8⁺ T cells from 100 ART-naïve PLHIV. Participants were classified into controls (baseline CD4⁺ > 200 cells/µL, n = 49) and cases (baseline CD4⁺ ≤ 200 cells/µL, n = 51). Cases were further categorised after 48 weeks of ART as immunological responders (IR, n = 34) or INR (n = 16) based on a recovery cut-off of 250 cells/µL. The research employed integrative proteomic and metabolomic analyses, adjusted for sex, complemented by miRNA and qRT-PCR validation in a subset of samples to identify differential molecular signatures.</p><p><strong>Results: </strong>In CD4⁺ T cells, a baseline signature of 381 proteins and 45 metabolites significantly differentiated controls from cases; notably, 34 proteins and 16 metabolites specifically discriminated future IR from INR before starting treatment. CD8⁺ T cells showed a more limited signature with minimal stratification between IR and INR. Integrative analysis revealed coordinated dysregulation in CD4⁺ T cells of INR, characterised by altered glycolytic flux, metabolic exhaustion, and oxidative stress. Exploratory analyses via miRNA and qRT-PCR confirmed these findings and suggested post-transcriptional mechanisms contribute to the impairment.</p><p><strong>Conclusions: </strong>Incomplete immune recovery in PLHIV is primarily driven by pre-existing metabolic dysfunction and oxidative stress within CD4⁺ T cells, rather than CD8⁺ T cells. These findings identify specific molecular signatures present before ART initiation, highlighting early potential therapeutic targets and strategies to enhance immune reconstitution in this vulnerable population.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182924","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":"Fibroblast-associated protection against hypoxia and carboplatin-induced cytotoxicity during coculture with osteosarcoma.","authors":"Hans Zoellner, Duan Ni, Jhati Kakani, Jingyi Zhou, Brigitta Sabrina Auwyang, Yogambha Ramaswamy, Belal Chami","doi":"10.1186/s10020-026-01596-0","DOIUrl":"https://doi.org/10.1186/s10020-026-01596-0","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma progression and treatment resistance are strongly influenced by the tumour microenvironment. One of the key players in tumour microenvironments is cancer-associated fibroblast. Much of the conventional cancer-associated fibroblast-centred research paradigm focuses on the secretory and matrix-remodelling aspects of fibroblasts. However, less is known on how fibroblasts influence osteosarcoma cell behaviour, particular under stress.</p><p><strong>Methods: </strong>In a proof-of-concept study, human dermal fibroblasts and osteosarcoma cells were studied using direct coculture and size-restricted transwell systems. Fluorescent labelling, confocal microscopy, live-cell imaging, and single-cell tracking were used to assess intercellular transfer, migratory behaviour, proliferation, and survival under chemotherapy and hypoxic challenge.</p><p><strong>Results: </strong>Osteosarcoma cells acquired fibroblast-derived, mitochondria cargo-enriched material in both direct and indirect coculture systems, with transfer of material enhanced under carboplatin and hypoxic stress. Notably, fibroblast coculture increased osteosarcoma cell migration and promoted survival under stress but did not substantially increase basal proliferation.</p><p><strong>Conclusions: </strong>These findings suggest that fibroblast-to-cancer cell transfer of mitochondria-enriched cargo is accelerated during stress conditions with the concomitant observation of proportional osteosarcoma protection to degree of fibroblast cargo transfer. Further research should examine stress-amplified transfer during tumour adaptation, chemoresistance, and metastatic behaviour, potentially highlighting stromal intercellular communication as an important aspect of osteosarcoma biology.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112085","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":"A TRIM15-CDX2 loop drives bile acid-induced gastric intestinal metaplasia.","authors":"Dan Wang, Jian Chen, Wei Xu, Sachin Mulmi Shrestha, Qin Lu, Lihua Ren, Qinghua Ji, Hailu Wu, Ruihua Shi","doi":"10.1186/s10020-026-01578-2","DOIUrl":"10.1186/s10020-026-01578-2","url":null,"abstract":"<p><strong>Background: </strong>Gastric intestinal metaplasia (GIM), a precancerous lesion and risk factor for gastric cancer, is closely associated with chronic bile acid (BA) exposure; however, its molecular mechanisms remain unclear. This study aimed to identify key regulators involved in BA-associated GIM and to elucidate their functional roles.</p><p><strong>Methods: </strong>TRIM15 and GIM markers (CDX2, MUC2, KLF4, and VIL1) were assessed in human GIM and paired normal tissues by RNA-seq, RT‒qPCR, Western blotting (WB), and immunofluorescence (IF). BA profiles were analyzed using UHPLC‒MS/MS. In vitro, GES-1 cells were treated with CDCA and subjected to TRIM15 gain- and loss-of-function assays. CDX2-mediated transcriptional regulation of TRIM15 was evaluated by dual-luciferase reporter and ChIP assays. NF-κB signaling and related proteins were assessed by WB and IF. The interaction between TRIM15 and IκBα and the levels of ubiquitination were investigated by coimmunoprecipitation, LC-MS/MS and protein-protein docking analysis. Functional assays were used to assess proliferation and apoptosis. In vivo validation was performed using an AAV9-mediated TRIM15 knockdown rat model.</p><p><strong>Results: </strong>TRIM15 expression was consistently upregulated in GIM and increased stepwise with disease severity, accompanied by a positive association with CDX2 expression. BA profiling revealed the selective enrichment of cholic acid (CA) and chenodeoxycholic acid (CDCA), which induced GIM-associated phenotypes in vitro. Mechanistically, CDX2 directly bound to the TRIM15 promoter to increase its transcription, whereas TRIM15 promoted CDX2 expression via the NF-κB pathway, resulting in the formation of a regulatory loop. Further mechanistic analyses revealed that TRIM15 promoted K48-linked ubiquitination and subsequent proteasomal degradation of IκBα, thereby enhancing p65 phosphorylation. Notably, this effect was abolished by expression of the degradation-resistant IκBα S32A/S36A mutant. In vivo, TRIM15 knockdown attenuated gastric mucosal injury and intestinal metaplasia and reduced NF-κB signaling and CDX2 expression.</p><p><strong>Conclusion: </strong>These findings suggest the involvement of a TRIM15-NF-κB-CDX2 regulatory loop in BA-associated GIM. TRIM15 may contribute to epithelial reprogramming under BA exposure and could be a potential biomarker and therapeutic target for GIM progression.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183006","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":"P1D6 inhibits FnBP-induced extracellular proteome remodeling: proteomic evidence for a novel intervention strategy in atopic dermatitis.","authors":"Chang Xu, Ziyi Hu, Yixuan Liu, Jiashuo Huang, Xueshan Cao, Yang Guo","doi":"10.1186/s10020-026-01590-6","DOIUrl":"10.1186/s10020-026-01590-6","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is an inflammatory skin disorder characterized by skin barrier impairment, chronic inflammation, and intense pruritus. Staphylococcus aureus (S. aureus) critically contributes to its pathogenesis; however, the mechanistic role of its virulence factor fibronectin-binding protein (FnBP) in keratinocytes remains poorly understood. This study used bibliometric analysis and quantitative proteomics to examine the relationship. We first performed a bibliometric analysis, revealing a sustained increase in publications on S. aureus and AD, peaking at 99 articles in 2023, with hotspots focused on skin barrier function, immune inflammation, and pediatrics. Quantitative proteomics was employed to investigate how FnBP reshapes the extracellular proteome and whether the anti-α5 integrin antibody P1D6 exerts interventional effects. HaCaT cells were stimulated with recombinant FnBP alone or in combination with P1D6, followed by data-independent acquisition (DIA)-based proteomic analysis of secretome changes. Proteomic analysis identified FnBP-induced differentially expressed proteins enriched in immune- and barrier-related pathways, including cell adhesion, cell junctions, and VEGFA-VEGFR2 signaling. P1D6 intervention significantly inhibited the secretome profile and identified 241 core responsive proteins, of which approximately 52% returned to baseline levels after intervention (P > 0.05). These proteins were primarily enriched in pathways governing protein homeostasis, folding, proteasomal degradation, and interleukin-7 signaling. Notably, P1D6 modulated the downregulation of ATP5F1B and P4HB, key effectors within the interleukin-7 pathway. This study demonstrates that FnBP remodels the keratinocyte secretome by disrupting protein homeostasis, consequently inducing barrier injury and chronic inflammation related to AD, which can be effectively blocked by P1D6. Combined with bibliometric trends and proteomic evidence, this study focuses on FnBP, an underexplored virulence factor, and provides novel insights into AD pathogenesis and therapeutic interventions.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875414","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":"Drugs inducing interstitial lung disease: in silico analysis of their structures and targets.","authors":"Mao Tanabe, Shokichi Takahama, Takuya Yamamoto, Ryuichi Sakate","doi":"10.1186/s10020-026-01559-5","DOIUrl":"10.1186/s10020-026-01559-5","url":null,"abstract":"<p><strong>Background: </strong>The molecular mechanisms underlying many drug-induced diseases, namely, the adverse effects caused by medications, remain poorly understood. As we consider that adverse effects result from the unintended targets of a drug, we aimed to clarify the molecular mechanisms of drug-induced diseases based on information regarding off-target interactions.</p><p><strong>Methods: </strong>First, off-targets were searched in public databases, and four proteins were selected. Subsequently, rare and intractable diseases caused by drugs targeting the proteins were identified through side-effect information. Further, the pharmacological actions of the drugs on the targets and related substructures were investigated using statistical analysis and substructure search.</p><p><strong>Results: </strong>Of the four proteins, one of the ATP-binding cassette (ABC) transporters, ABCG2, was related to a severe disease, interstitial lung disease (ILD): drugs inducing ILD showed a strong tendency to bind and inhibit ABCG2 and kinases. Moreover, these drugs tended to contain pyrimidine and methoxyethane, both of which are effective at inhibiting ABCG2 and kinases, as substructures. Drugs satisfying both conditions of \"binding to ABCG2/kinase\" and \"having substructure pyrimidine/methoxyethane\" were more associated with ILD compared with drugs satisfying only one condition. Among the drugs reported to be associated with a high incidence of ILD, many were strong inhibitors of ABCG2 with or without kinase inhibitory activity; however, some drugs showed little evidence of binding to ABCG2 or kinases. Examples of the latter included folic acid (FA) antagonists, which are known to induce pulmonary fibrosis.</p><p><strong>Conclusions: </strong>These results suggest that for kinase inhibitors known to induce ILD, inhibition of off-target ABCG2 as well as kinases is likely to be associated with the disease and that many drugs inducing ILD other than known kinase inhibitors also inhibit ABCG2. Some drugs with little evidence of binding to ABCG2 include antifolates, raising the possibility that abnormal FA metabolism is one of the common phenomena of drug-induced ILD, particularly as ABCG2 is a folate efflux transporter related to tissue folate absorption.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}