Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"SREBF2 promotes mitophagy and protects against ferroptosis via Cav-1-regulated PINK1/Parkin signaling in ischemic heart failure.","authors":"Jia Li, Jia Liu, Fanyan Luo, Chengliang Zhang, Wen Hu, Wei Liu","doi":"10.1007/s00109-026-02707-4","DOIUrl":"10.1007/s00109-026-02707-4","url":null,"abstract":"<p><p>Myocardial infarction-induced heart failure (MI-HF) remains a major contributor to cardiovascular mortality, yet the molecular mechanisms underlying its progression, particularly those involving ferroptosis, are not fully understood. This study aimed to investigate the role of SREBF2 in regulating ferroptosis and mitochondrial homeostasis in MI-HF. Differentially expressed genes were screened from the GSE24519 dataset and overlapped with ferroptosis-related genes, identifying SREBF2 as a potential target. SREBF2 expression was examined in human HF samples, MI-HF mice, and oxygen-glucose deprivation (OGD)-injured cardiomyocytes. Functional roles of SREBF2 were evaluated through in vivo overexpression in mice and in vitro assays in cardiomyocytes. Ferroptosis markers (GPX4, ACSL4, ROS, MDA, Fe²⁺, GSH), mitochondrial membrane potential (ΔΨm), and mitophagy-related proteins (PINK1, Parkin, p62) were assessed. Chromatin immunoprecipitation and rescue experiments were conducted to confirm the transcriptional regulation of Caveolin-1 (Cav-1) by SREBF2. SREBF2 was significantly downregulated in MI-HF tissues and OGD-injured cardiomyocytes. Overexpression of SREBF2 improved cardiac function, reduced infarct size and fibrosis, and enhanced myocardial remodeling in MI-HF mice. SREBF2 suppressed ferroptosis by reducing ROS, Fe²⁺, and MDA levels, restoring GSH and GPX4, and downregulating ACSL4. Mitochondrial dysfunction was alleviated via improved ΔΨm, reduced mitoROS, and balanced mitochondrial dynamics. SREBF2 activated PINK1/Parkin-mediated mitophagy, which was essential for its anti-ferroptotic effects. Mechanistically, SREBF2 directly bound to and transcriptionally activated Cav-1, which mediated downstream mitophagy activation and ferroptosis inhibition. Cav-1 knockdown or mitophagy inhibition abrogated SREBF2-induced mitochondrial protection and cytoprotection. The results of our study demonstrate that SREBF2 mitigates MI-induced HF by activating the Cav-1/PINK1/Parkin axis to promote mitophagy and inhibit ferroptosis. These findings reveal a novel cardioprotective mechanism and identify SREBF2 as a promising therapeutic target in heart failure.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual roles of lysine-specific demethylase 1 (KDM1A/LSD1) in the modulation of tumor immune microenvironment and its inhibitors in colorectal cancer.","authors":"Yuan-Ying Wang, Wei-Wei Zhou, Gang Jia, Xiao-Mei Huang, Zhi-Yu Song","doi":"10.1007/s00109-026-02708-3","DOIUrl":"10.1007/s00109-026-02708-3","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have demonstrated significant potential in cancer therapy. However, the immunosuppressive nature of the tumor microenvironment (TME) and ICI remains a major challenge in clinical treatment. Recently, epigenetic regulators, such as the histone demethylase Lysine (K)-Specific Demethylase 1 A(KDM1A/LSD1), have participated in tumor progression and immune evasion by reshaping the epigenetic state of tumor cells and the immune microenvironment. This study systematically reviewed the dual role of KDM1A in colorectal cancer (CRC). On one hand, KDM1A can promote tumor cell proliferation and aberrant differentiation by regulating signaling pathways, such as Wnt/β-catenin and Notch. On the other hand, it can also modulate the functions of T cells, B cells, macrophages, and Natural Killer (NK)cells through epigenetic modifications, thus inhibiting antitumor immune responses and creating an immunosuppressive microenvironment. Notably, KDM1A can reduce the immunogenicity of CRC by downregulating tumor antigen presentation or pro-inflammatory cytokine secretion, thus enhancing the tumor's resistance to ICI. Clinically, small-molecule inhibitors targeting KDM1A, such as Tranylcypromine (TCP) and Iadademstat, could enhance the efficacy of ICIs by reversing the immunosuppressive microenvironment, especially in mismatch repair proficient (pMMR) CRC. Future studies should further elucidate the molecular networks of KDM1A regulating immunogenicity and explore the synergistic mechanisms of its inhibitors with other epigenetic drugs or immunotherapies in order to provide new strategies for overcoming CRC resistance to immunotherapies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming growth factor-β1 promotes initiation of entheseal pathological bone formation via osteonectin induction in ankylosing spondylitis.","authors":"Sungsin Jo, Dongju Kim, Sung Eun Wang, Chanhyeok Jeon, Dabin Kim, Hye-Ryeong Jo, Seung Hoon Lee, Sang Mok Jung, Sung Hoon Choi, Tae-Hwan Kim","doi":"10.1007/s00109-026-02705-6","DOIUrl":"10.1007/s00109-026-02705-6","url":null,"abstract":"<p><p>Ankylosing spondylitis (AS) is an inflammatory disease marked by aberrant new bone formation and spinal ankylosis. Transforming growth factor-β1 (TGFβ1) is implicated in osteogenesis, yet its downstream effectors in AS remain unclear. Osteonectin, a glycoprotein secreted by osteoblasts, plays a critical role in bone formation with TGFβ1, but has not been studied in AS. This study aimed to investigate the TGFβ1-osteonectin mediated regulation of osteogenic activity in AS. Serum levels of TGFβ1, osteonectin, and osteocalcin were measured in AS patients and healthy controls. Measured these serum levels were compared with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Enthesis cells isolated from AS spinal tissues were stimulated with recombinant TGFβ1 in vitro. Proliferation, matrix production, migration, and clonogenicity were evaluated. Immunohistochemical staining of spinal tissues was performed to assess osteonectin expression. AS patients showed significantly elevated serum levels of TGFβ1 and osteonectin compared to healthy controls. Osteonectin expression, but not osteocalcin, was significantly correlated with serum level of TGFβ1. TGFβ1 stimulation enhanced proliferation, collagen deposition, migratory capacity, and colony formation in enthesis cells derived from AS patients. Immunohistochemistry revealed increase of osteonectin expression in periosteal regions of AS tissues. These findings suggest that osteonectin is a TGFβ1-responsive effector involved in early osteoprogenitor activation and may contribute to pathological bone formation in AS. Osteonectin represents a potential biomarker and therapeutic target for early structural progression in AS.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148687602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E-cigarette vaping is associated with pro-fibrotic gene expression in kidney and liver tissues.","authors":"Wanjun Gu, Howard Chang, Poorvi Saini, Samvel Gaboyan, Jarod Olay, Jorge A Masso-Silva, John Shin, Ira Advani, Ashley Du, Cameron Brand, Joan Heller Brown, Alexia Perryman, Laura E Crotty Alexander","doi":"10.1007/s00109-026-02699-1","DOIUrl":"10.1007/s00109-026-02699-1","url":null,"abstract":"<p><p>Conventional tobacco use causes a wealth of diseases and adversely affects cells and organ systems across the body. The long-term effects of e-cigarette vaping on the same remain unclear. Identifying early pathogenic signals at the organ level via animal models may shed light on potential downstream effects in humans. Here we investigate transcriptomic changes in the kidney and liver, organs known to be damaged by long-term combustible tobacco use, of mice exposed daily to e-cigarette aerosols (vapor) with or without nicotine. C57BL/6 male 6-8 week-old mice underwent whole-body exposure to room air, e-cigarette (3rd generation box mod) vapor containing 70:30 propylene glycol and glycerin (PG: Gly) without nicotine (Vehicle), and e-cigarette vapor with 6 mg/mL freebase nicotine in 70:30 PG: Gly (E-cig) for 1 h daily for 3 months. RNA sequencing on kidney and liver tissues and apriori gene set analysis were performed. Unbiased principal component analysis identified closer clustering of E-cig and Vehicle groups, relative to Air, in the kidney. Assessment of the a priori gene set found nicotine to be associated with greater transcriptomic changes in the kidney while vehicle chemicals induced greater changes in the liver. Alterations in expression of Car3 and Foxo3 identify oxidative stress and inflammation in the renal system associated with e-cigarette exposure, while dysregulated Il6ra and Lpin1 in the liver highlight disruptions in lipid metabolism and immune signaling. Chronic inhalation of e-cigarette vapor alters gene expression in downstream organs, in a pattern most consistent with promotion of fibrosis and metabolic dysregulation, underscoring the need to define long-term pathophysiologic effects of e-cigarette vaping across the body.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148633393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinase regulation of miRNA networks in cardiometabolic disease: emerging pathways to precision therapy.","authors":"Firdos Ahmad, Asima Karim, Meganathan Kannan, Rizwan Qaisar","doi":"10.1007/s00109-026-02704-7","DOIUrl":"10.1007/s00109-026-02704-7","url":null,"abstract":"<p><p>Cardiometabolic diseases remain a major global health burden, and current therapies only partially address the persistent residual risk driven by chronic inflammation, hypoxia, metabolic overload, and mechanical stress. A critical need is to understand how these diverse stress signals are integrated at the cellular and molecular levels to determine whether tissues adapt or undergo pathological remodeling. This review presents a comprehensive framework of kinase-microRNA (miRNA) crosstalk as an emerging regulatory axis in cardiometabolic disease. We discuss how stress-activated kinase pathways, including ERK, p38/JNK, PI3K-Akt-mTOR/S6K2, AMPK, GSK-3, and EGFR, reprogram miRNA output through phosphorylation of key components of the miRNA machinery, including DROSHA/DGCR8, DICER-TRBP, and AGO2. These phosphorylation-dependent mechanisms influence miRNA processing, substrate selection, RISC assembly, and target repression in a context-dependent manner. We further highlight the reciprocal regulation whereby miRNAs modulate kinase signaling pathways, establishing feedback networks that regulate inflammation, apoptosis, fibrosis, angiogenesis, and metabolic adaptation across cardiac, vascular, and immune cells. Emerging technologies, including AGO2 eCLIP, phosphoproteomics, CRISPR-based perturbations, and single-cell/spatial profiling, allow causal mapping of kinase-miRNA networks. Collectively, these advances establish kinase-miRNA crosstalk as a promising mechanistic framework and therapeutic target for precision intervention in heart failure, atherosclerosis, diabetic cardiomyopathy, and related cardiometabolic diseases.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pressure-mediated mechanosensitive Piezo2 channel is activated in neurogenic bladder and promote bladder fibrosis in children.","authors":"Lei Lv, Yanping Zhang, Qi Li, Junkui Wang, Shuai Yang, Zhaokai Zhou, Shuai Li, Zhengguang Zhang, He Zhang, Xingchen Liu, Yibo Wen, Jian Guo Wen","doi":"10.1007/s00109-026-02701-w","DOIUrl":"10.1007/s00109-026-02701-w","url":null,"abstract":"<p><p>Mechanosensitive Piezo2 channels play a critical role in bladder pressure perception and may contribute to bladder fibrosis in patients with neurogenic bladder (NB), a condition that significantly affects quality of life. This study aimed to investigate the expression of Piezo2 and its role in bladder fibrosis using both human and animal models. Bladder tissue samples were obtained from children with NB undergoing ileocystoplasty, along with normal tissues from control subjects. An NB model was established in juvenile Sprague-Dawley rats through spinal nerve transection. Transcriptome analysis revealed the activation of pathways associated with mechanical stimulation, nuclear factor kappa-B (NF-κB) signaling, and epithelial-mesenchymal transition (EMT) in the context of NB. The results indicated that elevated Piezo2 levels were correlated with increased bladder pressure and fibrosis. Cystometry tests demonstrated significant increases in bladder pressure at week 2, followed by slight decreases, although pressure levels remained elevated compared to controls. Stretching experiments conducted on SV-HUC-1 cells showed that Piezo2 activation exacerbated fibrosis through the Ca²⁺/NF-κB/EMT axis, while the use of Piezo2 siRNA mitigated this effect. These findings suggest that Piezo2 channels, activated by increased pressure, accelerate bladder fibrosis via the Ca²⁺/NF-κB/EMT pathway, indicating that Piezo2 inhibition may serve as a potential therapeutic strategy to prevent fibrosis in NB.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"γδ T cells show distinct responses to CMV after stem cell transplantation.","authors":"Freya Sibbertsen, Zheng Song, Cedric Ly, Inga Sandrock, Stefan Bonn, Christian Koenecke, Likai Tan, Christian Schultze-Florey, Immo Prinz","doi":"10.1007/s00109-026-02703-8","DOIUrl":"10.1007/s00109-026-02703-8","url":null,"abstract":"<p><p>Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic stem cell transplantation (aHSCT) and critically shapes immune reconstitution. However, the clonal and functional dynamics of T cell responses to CMV remain insufficiently defined. In this study, we combined longitudinal single-cell RNA sequencing with paired T cell receptor sequencing to track γδ and αβ T cell clones at clonal resolution across five post-transplant time points in patients with and without CMV reactivation. This integrative approach revealed marked, patient-specific expansion of non-Vγ9Vδ2 γδ T cell clones, particularly within Vδ1⁺ and Vδ3⁺ subsets, which was associated with differentiation toward cytotoxic and antiviral effector states characterized by IFN-γ and TNF-α expression. Conventional CD8⁺ αβ T cells showed comparatively modest clonal dynamics during CMV reactivation in this cohort. Longitudinal tracking of individual clonotypes demonstrated heterogeneous but recurrent trajectories, with expanding γδ T cell clones frequently acquiring antiviral and cytotoxic phenotypes following CMV reactivation. These findings highlight the adaptive-like behavior and functional plasticity of non-Vγ9Vδ2 γδ T cells and provide a high-resolution framework for studying antiviral immune responses during immune reconstitution. KEY MESSAGES: Single-cell sequencing enables clonal tracking of T cells during CMV reactivation. γδ T cells show patient-specific clonal expansion after CMV reactivation. Expanding γδ T cell clones acquire antiviral and cytotoxic phenotypes. Vγ9Vδ2 γδ T cells remain stable with limited clonal expansion. αβ T cells display limited clonal responses during CMV reactivation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-intrinsic TLR4 signaling as a context-dependent rheostat in glioblastoma.","authors":"Thura Tun Oo","doi":"10.1007/s00109-026-02702-9","DOIUrl":"10.1007/s00109-026-02702-9","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains resistant to therapy due to cellular heterogeneity and adaptive stress responses, yet the role of tumor-intrinsic Toll-like receptor 4 (TLR4) signaling in this process remains unresolved. This review addresses a central inconsistency in the field by defining tumor-intrinsic TLR4 as a context-dependent signaling rheostat that generates distinct biological outcomes rather than a uniform tumor-promoting pathway. Across experimental systems, TLR4 signaling produces divergent effects that range from mesenchymal transition, invasion, and adaptive survival under chronic or therapy-associated conditions, to differentiation, apoptosis, and increased treatment sensitivity under specific cellular and temporal contexts. These opposing outputs are not contradictory but arise from defined determinants, including ligand environment, signaling dynamics, tumor cell state, and metabolic conditions. This framework explains previously discordant findings and establishes that the functional role of tumor-intrinsic TLR4 cannot be inferred from receptor activation alone. Instead, its impact is conditional and state-dependent. This perspective defines a clear experimental and translational priority: to identify the contexts in which tumor-intrinsic TLR4 signaling sustains tumor persistence versus exposes therapeutic vulnerability, thereby enabling rational and stratified intervention strategies in GBM.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148475707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis reveals divergent inflammatory mechanisms of COVID-associated Guillain-Barré syndrome.","authors":"Can Ulutekin, Amelie Can, Lenka Súkeníková, Luis Querol, Raul Juntas-Morales, Arnau Llauradó, Anelia Dietmann, Tobias Weiss, Daniela Latorre, Burkhard Becher, Florian Ingelfinger, Bettina Schreiner","doi":"10.1007/s00109-026-02698-2","DOIUrl":"10.1007/s00109-026-02698-2","url":null,"abstract":"<p><p>Guillain-Barré syndrome (GBS) is an acute immune-mediated neuropathy triggered by infections, with poorly understood pathophysiological diversity. COVID-19-associated GBS (COVID-GBS) is a rare but severe post-infectious condition, and its immune mechanisms remain unclear. We profiled immune mediators in cerebrospinal fluid (CSF) and serum from COVID-GBS patients, comparing them to non-COVID GBS (Control-GBS), COVID-19 patients without neurological complications (COVID-no-GBS) and non-inflammatory neuropathy controls (Neuropathy-no-GBS). To gain mechanistic insights, we integrated publicly available single-nucleus transcriptomic data from sural nerve biopsies of neuropathy patients. IL-8 was confirmed as a key cytokine in GBS. Analysis of publicly available single-nucleus transcriptomic data from non-GBS sural nerve biopsies suggested myeloid cells as potential sources of IL-8, with evidence of autocrine signaling capacity. LIF and CD8A emerged as novel biomarkers, with this transcriptomic analysis indicating that LIF receptor components are expressed on endothelial and stromal cells, suggesting these as potential cellular targets. COVID-GBS patients exhibited unique CSF alterations and distinct serum profiles marked by altered NK cell activity, cytotoxic T-cell responses, and myeloid differentiation. Moreover, associations between inflammatory, extracellular matrix, and regulatory markers with clinical disability differed between COVID-GBS and Control-GBS, pointing to divergent immune mechanisms. Our findings suggest that GBS involves myeloid-driven cytokine responses and local LIF signaling. Analysis of publicly available transcriptomic data from non-GBS sural nerve biopsies suggests potential cellular sources and targets, though validation in GBS-affected tissue is needed. COVID-GBS features a distinct immune signature involving localized and systemic inflammation. These insights deepen our understanding of GBS pathogenesis and nominate candidate biomarkers for further validation and potential therapeutic targeting.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148383479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the target: implications of Wnt pathway inhibitors on bone health.","authors":"Clement Nachef, Arnaud Vanjak, Eric Haÿ, Martine Cohen-Solal, Thomas Funck-Brentano","doi":"10.1007/s00109-026-02697-3","DOIUrl":"10.1007/s00109-026-02697-3","url":null,"abstract":"<p><p>Wnt signaling inhibitors are under investigation as potential therapies for conditions characterized by upregulated Wnt signaling, such as cancers, hematological disorders, and organ fibrosis. However, because the Wnt pathway is essential for bone homeostasis, its inhibition can adversely affect skeletal health. This review focuses on the bone-related off-target effects of Wnt inhibitors currently in clinical development, specifically those evaluated in Phase I and II trials with available published data. We found that inhibitors targeting upstream components of the pathway-such as Wnt ligands or receptors (e.g., porcupine inhibitors, Ipafricept, or Vantictumab)-frequently lead to bone-related adverse effects, including fractures and early trial termination. Co-administration of bisphosphonates may help mitigate these effects. In contrast, downstream inhibitors (e.g., PRI-724, niclosamide) have not been linked to bone toxicity, although this may reflect either underreporting or a genuinely lower skeletal impact. Further preclinical studies are warranted to better understand these differential effects. A thorough understanding of bone-specific risks is critical as Wnt signaling inhibitors continue to advance in clinical development.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148383490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}