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

{"title":"Nuclear factor IX promotes endometriosis progression through transcriptional activation of tetraspanin-2.","authors":"Yuqi Liu, Qing Xue, Jingwen Zhu, Cheng Zeng, Xin Li, Jing Shang, Jie Li, Peili Wu","doi":"10.1007/s00109-026-02665-x","DOIUrl":"10.1007/s00109-026-02665-x","url":null,"abstract":"<p><p>Endometriosis is a benign yet aggressive disease characterized by enhanced proliferation and invasion of ectopic endometrial tissue. Identifying upstream regulators that co-regulate these processes will provide novel insights into endometriosis pathogenesis and potential therapeutic targets. In this study, by integrating public single-cell RNA-seq data with our own RNA sequencing data, we identified nuclear factor IX (NFIX) as predominantly enriched in endometriotic stromal cells (ESCs), correlating with enhanced proliferative and invasive capacities. However, the underlying molecular mechanisms remain to be elucidated. Using the Venny platform, we intersected NFIX target genes from the KnockTF2.0 database with differentially expressed genes from our RNA sequencing data. Among these overlapping genes, we further identified tetraspanin-2 (TSPAN2) as a target of NFIX and validated that increased TSPAN2 expression mediated the regulatory effects of NFIX on ESCs' proliferation and invasion. Mechanistically, we found that NFIX exerts a significant stimulatory effect on TSPAN2 expression in ESCs. Luciferase reporter assays using serial deletion mutants confirmed that NFIX specifically binds to the -408 ~ -400 bp region of the TSPAN2 promoter, activating its transcription. Additionally, a chromatin immunoprecipitation (ChIP) assay revealed that the binding affinity of NFIX for the -408 ~ -400 bp region of the TSPAN2 promoter was higher in ESCs than in eutopic endometrial stromal cells (EMs). Moreover, NFIX knockdown in endometriosis mice downregulated TSPAN2 expression and inhibited ectopic lesion growth. Overall, this study demonstrated that NFIX promotes proliferation and invasion of ESCs by transcriptionally activating TSPAN2, suggesting NFIX as a potential therapeutic target. KEY MESSAGES: NFIX expression was markedly higher in ESCs than in EMs, correlating with increased proliferation and invasion capabilities. TSPAN2 was identified as a key mediator of NFIX-dependent regulation of proliferation and invasion of ESCs. NFIX transcriptionally activated TSPAN2 by binding to the -408 to -400 bp region of its promoter. In vivo knockdown of NFIX significantly inhibited the growth of endometriotic lesions in mice.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13179170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147950689","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":"Molecular and statistical weaknesses of the p-tau217/Aβ_1-42 plasma ratio for alzheimer's diagnosis.","authors":"Christian Griñán Ferré, Mercè Pallàs, Rafael Franco","doi":"10.1007/s00109-026-02676-8","DOIUrl":"10.1007/s00109-026-02676-8","url":null,"abstract":"<p><p>The FDA's approval of the Lumipulse G p-tau217/Aβ_1-42 plasma ratio enhances access to Alzheimer's diagnostics but risks confusing convenience with biological accuracy. The assay is scalable and non-invasive, yet it relies on a ratio of two markers that are unstable and only partly specific to the disease, raising concerns about reproducibility and interpretation. The reported performance is solid in carefully selected groups, but is likely to be less robust in broader real-world populations with lower disease prevalence, mixed pathologies, and higher comorbidity. If biomarker-based enrollment is shaped by imperfect specificity, misclassification may propagate into trial recruitment, treatment-effect estimates, and downstream validation. This concern is amplified when biomarkers are validated within partially circular frameworks in which plasma assays, positron emission tomography, cerebrospinal fluid markers, and clinical diagnosis reinforce one another without fully independent neuropathological confirmation. Blood-based assays remain promising, but their clinical use should be guided by rigorous analytical scrutiny, broad validation across diverse populations, standardized pre-analytical handling, and transparent data sharing. The aim of biomarker science should be not striking receiver operating characteristic curves in curated cohorts, but biological fidelity across human heterogeneity and validation grounded in mechanism. Until then, the p-tau217/Aβ_1-42 ratio is best regarded as a useful contextual or research tool rather than a standalone diagnostic benchmark, so that precision medicine does not rest on associations whose causal and mechanistic basis remains insufficiently established. Its most appropriate use may be in longitudinal monitoring within the same individual, where changes over time may be more informative than a single threshold-based diagnostic result.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13161342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876854","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":"Correction to: Spil mediated sEH overexpression contributes to the senescence of alveolar epithelial cells during pulmonary fibrosis in mice.","authors":"Chen-Yu Zhang, Wen-Jing Zhong, Jin-Tong Yang, Yan-Ling Qiu, Han-Xi Sha, An-Jun Ou, Yu-Biao Liu, Xiao-Ting Huang, Yong Zhou, Jia-Xi Duan, Cha-Xiang Guan","doi":"10.1007/s00109-026-02678-6","DOIUrl":"https://doi.org/10.1007/s00109-026-02678-6","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849111","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":"Fibrotic microRNAs in the suppression of HSC activation and ECM deposition to facilitate the regression of hepatic fibrosis in zebrafish.","authors":"Yu-Heng Lai, Mu-Kuang He, Chung-Tsui Huang, Han-Yu Tseng, Tzu-Ching Lin, Ting-Yu Yang, Semon Wu, Guor Mour Her","doi":"10.1007/s00109-026-02672-y","DOIUrl":"10.1007/s00109-026-02672-y","url":null,"abstract":"<p><p>During liver injury, early pathological changes may go unnoticed, delaying the diagnosis until the disease has advanced to stages such as fibrosis, cirrhosis, or hepatocellular carcinoma. Hepatic fibrosis is a sign of long-term liver injury that leads toward permanent liver damage. It involves the buildup of too much extracellular matrix (ECM) and is activated by hepatic stellate cells (HSCs). The transforming growth factor-β1 (TGF-β1)/SMAD pathway is central to this process, which shows great potential for therapeutic strategies. Therefore, we investigated the therapeutic potential of microRNA (miRNA)-mediated regulation of fibrogenesis by using zebrafish models. A group of fibrosis-related miRNAs was identified and used to generate transgenic zebrafish lines. Fibrosis was induced via doxycycline (DOX)-controlled overexpression of TGF-β1a, and the antifibrotic efficacy of miRNAs was evaluated. Quantitative real-time PCR showed a marked downregulation of the target miRNAs, accompanied by decreased expression of fibrotic markers. Next, we confirmed that TGF-β1a, GREM1, and α-SMA protein levels were decreasing. Histological staining revealed improved liver structure and diminished collagen deposition. These findings indicate that through manipulating the miRNA expressions, we can effectively disrupt TGF-β-induced fibrogenesis, inactivate HSC, inhibit ECM remodeling, and attenuate liver fibrosis, and highlight the potential of miRNA-based therapeutic strategies for early intervention in liver disease. KEY MESSAGES: Establishment of an in vivo model for developing an inducible miRNA expression system in zebrafish. Predicting and evaluating targeted miRNAs that attenuate TGF-β-induced hepatic fibrosis. Elucidate the potential mechanism for fibrosis that may be a strategy for future therapies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795061","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":"Pan-cancer ex vivo target evaluation of phosphodiesterase 3 A (PDE3A).","authors":"Kiesha Rice, Noora Lehtinen, Eetu Välimäki, Janne Suhonen, Pekka Taimen, Kimmo Kettunen, Sami Ventelä, Juha Kononen, Harri Sihto, Juha K Rantala","doi":"10.1007/s00109-026-02677-7","DOIUrl":"10.1007/s00109-026-02677-7","url":null,"abstract":"<p><p>Phosphodiesterase 3 A (PDE3A) is a well-characterized enzyme that plays a crucial role in various cellular processes, including cAMP-mediated signaling, CREB-mediated induction of p21 and signaling through protein kinases A and G. PDE3A has also been suggested as an inflammation-associated stemness gene which upon interaction with protein SLFN12, leads to blocked protein translation and induction of apoptosis. PDE3A has been found to be highly expressed in several human cancer types including sarcomas, pancreatic ductal adenocarcinoma, non-small cell lung cancer and melanoma. PDE3A has thus emerged as a potential therapeutic cancer target. However, to fully understand the functional role and validate target potential of PDE3A in different human cancers, further research is needed. We report here a pan-cancer ex vivo study of PDE3A protein expression across 24 different cancer types represented by 59 different molecular subtypes correlated with ex vivo drug screening of PDE3A-SLFN12 molecular glue anagrelide in 250 patient derived functional tumor models. Results of the study identify highest PDE3A expression in melanomas and across different histological subtypes of sarcomas. Correlating with the expression profile of PDE3A, anagrelide was found to display best therapeutic potential in sarcomas with high protein expression of both PDE3A and SLFN12, though sarcoma heterogeneity warrants further subtype-specific validation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795066","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":"The role and mechanism of TNFRSF21 in promoting necroptosis of vascular endothelial cells and inducing vascular leakage in sepsis.","authors":"Juntao Wang, Bindan Zhang, Yujia Wu, Weichao Li, Yuxi Zhang, Daiqin Bao, Haoyu Pei, Caifeng Shi, Han She, Xiaoyan Wang, Qingxiang Mao, Cong Yu","doi":"10.1007/s00109-026-02675-9","DOIUrl":"10.1007/s00109-026-02675-9","url":null,"abstract":"<p><p>Vascular leakage in sepsis is critical factors in improving the prognosis of septic patients, with limited treatment options targeting underlying molecular mechanisms. Necroptosis is a form of cell death centered around the RIPK1/RIPK3/MLKL pathway, combining both programmed and inflammatory characteristics. However, its role and mechanism in sepsis-induced vascular leakage remain unclear. In vivo and in vitro, CLP and LPS were used to simulate sepsis model. It was found that the expression levels of RIPK1/RIPK3/p-MLKL in septic VECs were significantly increased, and necroptosis inhibitors significantly improved septic vascular leakage. Transcriptomic and Western blot results suggested that TNFRSF21 plays a key role in necroptosis. shTNFRSF21 inhibited the formation of necrosome (RIPK3/p-MLKL) in septic VECs, improved vascular leakage in septic rats, and prolonged their survival time. The compound Phen-DC3 of inhibiting TNFRSF21 and the anesthetic remimazolam, both downregulated TNFRSF21, thereby improving septic vascular leakage. Our results suggest that TNFRSF21-regulated necroptosis plays an important role in septic vascular leakage, and targeting TNFRSF21 inhibition may be a potential therapeutic strategy for septic vascular leakage. KEY MESSAGES: Necroptosis plays a crucial role in sepsis-induced vascular leakage. TNFRSF21 promotes necrosome formation by upregulating RIPK3/p-MLKL, leading to endothelial cell death and disruption of the vascular barrier. The TNFRSF21 inhibitor Phen-DC3 was identified as a compound that improves sepsis-induced vascular leakage, providing a potential new therapeutic strategy for sepsis treatment. The anesthetic remimazolam inhibits TNFRSF21, improving sepsis-induced vascular leakage, offering experimental evidence for the repurposing of existing drugs like remimazolam in the treatment of sepsis.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795086","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":"Correction to: Gsα deficiency in macrophages promotes tumor progression via the MAPK signaling pathway.","authors":"Wenjiang Yan, Jingjing Yang, Siyu Tan, Tixiao Wang, Rong Xiao, Na Li, Min Chen, Lee S Weinstein, Lifan He, Chang Ma, Jingsu Zhang, Lifen Gao, Xiaohong Liang, Xiaojia Song, Wencheng Zhang, Chunhong Ma","doi":"10.1007/s00109-026-02673-x","DOIUrl":"10.1007/s00109-026-02673-x","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795054","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":"Live-cell imaging reveals decreased cAMP in a PFE-associated c.1050-3C>G PTH1R cell model.","authors":"K Marnet, H Subramanian, M Wiesler, A Borst, D Liedtke, G Pattappa, D Docheva, V O Nikolaev, A Stellzig-Eisenhauer, M Eigenthaler, M Herrmann","doi":"10.1007/s00109-026-02668-8","DOIUrl":"10.1007/s00109-026-02668-8","url":null,"abstract":"<p><p>Primary failure of eruption (PFE) is a rare autosomal disorder provoked by heterozygous mutations in the parathyroid hormone receptor 1 (PTH1R) gene. PTH1R is a G protein-coupled receptor (GPCR) which regulates intracellular signaling molecules like cAMP. By using CRISPR/Cas9, the pathogenic PTH1R variant, c.1050-3C>G, was introduced into the periodontal ligament (PDL-hTERT) cell line to investigate molecular mechanisms in a PFE in vitro model. The PDL-hTERT immortal cell line, derived from human primary PDL cells, is a well-established model for dental diseases and expresses PTH1R. We performed different functional assays to compare the behavior of the PDL-hTERT WT versus PTH1R-mutated cells. cAMP synthesis and PKA activation were compared between different cell lines by live-cell imaging using Förster Resonance Energy Transfer (FRET)-based biosensors. Phosphorylation of VASP was measured to validate and compare the PKA activation between the cell lines. In summary, our experiments show that the mutated cell line has no major phenotypic changes, but the PTH1R downstream signaling cascade is impaired. KEY MESSAGES: A rare autosomal disorder linked to mutations in the PTH1R gene, which encodes a G protein-coupled receptor regulating intracellular signaling, including cAMP production. The pathogenic PTH1R mutation (c.1050-3C>G) was introduced into a periodontal ligament (PDL hTERT) cell line to model PFE and study molecular mechanisms in vitro. Functional assay revealed that while the mutated cell line displayed no major phenotypic changes, the PTH1R downstream signaling cascade, including cAMP synthesis and PKA activation, was disrupted. Techniques like FRET-based biosensors and VASP phosphorylation assays highlighted specific impairments in signaling pathways in cells with the PTH1R mutations.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725519","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":"Correction to: Diacerein improves liver fibrosis, steatosis, and atherosclerosis in ApoE knockout mice.","authors":"Jie-Eun Lee, Isom Jin, Jung-Jae Lee, Jisu Jung, Jee-In Lee, Bo-Rahm Kim, Tae Jung Oh, Yun Kyung Lee, Sung Hee Choi","doi":"10.1007/s00109-026-02674-w","DOIUrl":"10.1007/s00109-026-02674-w","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680014","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":"GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.","authors":"Ayushi Sood, Joshua Peterson, Jayashree Jena, Vamsi Challa, Caden Washburn, Randy J Seeley, Renata O Pereira","doi":"10.1007/s00109-026-02671-z","DOIUrl":"10.1007/s00109-026-02671-z","url":null,"abstract":"<p><p>Growth differentiation factor 15 (GDF15) is a cytokine induced in several tissues in response to stress. GDF15 suppresses food intake and increases energy expenditure via its actions on the glial-derived neurotrophic factor receptor α family-like specific receptor (GFRAL), located in the hindbrain. We recently showed that selective deletion of the mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes (OPA1 BKO) leads to GDF15 secretion, partially mediating resistance to diet-induced obesity (DIO), and improving thermoregulation. To investigate whether GDF15 signaling through GFRAL is necessary to mediate these metabolic effects, we crossed OPA1 BKO mice with GFRAL global knockout mice (DKO). Under isocaloric conditions, DKO mice had similar body weight as control and OPA1 BKO mice. Upon high-fat diet feeding, DKO mice were partially resistant to DIO, but lacked the improvement in glucose homeostasis and insulin sensitivity observed in OPA1 BKO mice. Finally, DKO mice were susceptible to cold-induced hypothermia, suggesting a role for GFRAL in core body temperature regulation in the OPA1 BKO mice. Our data reveals a novel BAT-GDF15-GFRAL axis that modulates resistance to DIO and improves thermoregulation in mice in the context of mitochondrial stress. KEY MESSAGES: OPA1 deletion induces a BAT-GDF15-GFRAL axis to regulate systemic metabolic homeostasis. GDF15-signaling through GFRAL partially mediates resistance to DIO in mice lacking OPA1 in BAT. GFRAL mediates GDF15's effects on energy homeostasis in DIO OPA1 BKO mice. GDF15-GFRAL signaling is required to maintain core body temperature in cold-exposed OPA1 BKO mice.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680039","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}