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

{"title":"Combined targeting poly (ADP-ribose) polymerase and receptor tyrosine kinase inhibits ovarian clear cell carcinoma progression through disrupted ribosome biogenesis.","authors":"Chiao-Yun Lin, An-Shine Chao, Angel Chao, Ren-Chin Wu, Alice L Yu, Chiung-Hui Fu, Yu-Chuan Teng, Ruby Yun-Ju Huang, Chyong-Huey Lai","doi":"10.1007/s00109-026-02638-0","DOIUrl":"10.1007/s00109-026-02638-0","url":null,"abstract":"<p><p>OCCC has extremely poor prognosis. ARID1A mutation-related chromatin remodeling errors are key molecular features of OCCC. Dysregulation of receptor tyrosine kinases-related signaling pathways is common in OCCC. Here we show that combination of niraparib and lenvatinib exhibits significant synergistic inhibitory effects against platinum-resistant OCCC cell lines, xenografts, patient-derived tumoroid (PDT) models, and prolonged survival in the platinum-refractory patient-derived xenograft (PDX) model. RNA-sequencing revealed the most differently expressed genes in PDX treated with a combination of niraparib and lenvatinib versus control were in structural ribosomal components. Selected differently expressed ribosomal proteins (RPs: RPS2, RPS5, RPS9, and RPL3) was validated using quantitative polymerase chain reaction. Nucleophosmin (NPM1) expression, which is involved in ribosome biogenesis, was inhibited by niraparib and lenvatinib. Our findings imply that combined niraparib and lenvatinib reduces platinum-resistant OCCC progression by attenuating Src phosphorylation, NPM1 expression and ribosome biogenesis. These results highlight the necessity for continued exploration of this promising treatment strategy, particularly in future clinical trials for platinum-resistant or platinum-refractory OCCC. KEY MESSAGES: The combination of niraparib and lenvatinib synergistically inhibits platinum-resistant OCCC. This combination prolongs survival in a platinum-refractory PDX model. RNA sequencing revealed that the most differentially expressed genes in PDX models treated with this combination were associated with structural ribosomal components. This combination suppresses Src phosphorylation, NPM1 expression, and ribosomal protein levels in OCCC.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"33"},"PeriodicalIF":4.2,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12830444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146042440","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":"Identification of cryptic KMT2A-PTD and other novel fusion genes by transcriptome sequencing alters molecular risk stratification in AML-NK.","authors":"Angeli Ambayya, Rozaimi Razali, Sarina Sulong, Yee Yee Yap, Veena Selvaratnam, Jameela Sathar, Rosline Hassan","doi":"10.1007/s00109-026-02639-z","DOIUrl":"10.1007/s00109-026-02639-z","url":null,"abstract":"<p><p>Acute myeloid leukaemia with normal karyotype (AML-NK) is a cytogenetically cryptic yet heterogeneous clinical subgroup that lacks structural chromosomal abnormalities. Although classified as an intermediate-risk group, AML-NK exhibits variability in patient outcomes, underscoring the need for refined molecular stratification. In this study, high-throughput deep sequencing was performed on 51 AML-NK patients, with a comprehensive analysis of a Southeast Asian cohort to identify cryptic and novel fusion genes potentially implicated in disease pathogenesis and prognosis. Two pipelines (Arriba and STAR-fusion) were utilised in this study, which identified 68 findings involving 27 fusion genes, of which approximately 70% (n = 19/27) were novel. The majority (85%) were intrachromosomal fusion events, and 26% involved non-coding RNAs. The most recurrent and novel fusions were LATS2::SAP18 (17.6%) and HOXA3::HOXA9 (15.7%). In addition, known prognostic fusion genes, KMT2A-PTD, NUP98::NSD1, and NPM1::MLF1, were detected. The integration of these prognostic fusion genes into the ELN 2022 criteria reclassified 73% (n = 8/11) of intermediate-risk patients as poor-risk. Notably, the presence of KMT2A-PTD and/or LATS2::SAP18 was associated with reduced overall survival (p = 0.039, Log-Rank), although this significance was not retained in multivariate analysis. This study's findings revealed the complexity of the AML-NK transcriptome, highlighting the utility of RNA sequencing for prognostic risk assessment and therapeutic strategy development. KEY MESSAGE: RNA-seq uncovered 27 fusion genes in AML-NK, 70% of which were novel. Recurrent LATS2::SAP18 and HOXA3::HOXA9 fusions were identified. Fusion-based ELN 2022 reclassified most intermediate-risk patients. RNA-seq enhances prognostic assessment in AML-NK.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"32"},"PeriodicalIF":4.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021047","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":"E2F7 targets S100A2 to suppress CD8⁺T cell activity in lung adenocarcinoma by regulating glutamine metabolism.","authors":"Xianchao Chen, Jinping Li, Qiang Zou, Bo Tang, Yun Huang, Bin Liao","doi":"10.1007/s00109-026-02637-1","DOIUrl":"10.1007/s00109-026-02637-1","url":null,"abstract":"<p><p>Malignant cells within the tumor microenvironment have developed numerous strategies to resist the CD8⁺T cell-driven immune response. This study focuses on the mechanism of E2F7/S100A2 axis modulating CD8⁺T cell activity in lung adenocarcinoma (LUAD). Bioinformatics analysis was used to screen for the gene of interest, S100A2, and its regulatory transcription factor E2F7. Expression analysis of S100A2, E2F7, CD8, and PD-L1 at mRNA and protein levels was conducted via qRT-PCR, western blot, or immunohistochemistry. The interaction between S100A2 and E2F7 was validated using dual-luciferase reporter assays and chromatin immunoprecipitation. The interaction between LUAD cells and CD8⁺T cells was explored to understand immune escape mechanisms. Glutamine metabolism (glutamine/glutamate/α-KG/NADPH/GSH levels) and cytotoxicity (LDH/ELISA) were assessed. The impact of the E2F7/S100A2 axis in vivo was examined with LUAD xenograft mouse model. S100A2 was upregulated in LUAD tissues and cells and negatively correlated with CD8⁺T cell infiltration. Enhanced S100A2 expression could modulate glutamine metabolism to dampen the cytotoxic effects of CD8⁺T cells. E2F7 transcriptionally activated S100A2. In animal models, E2F7 knockdown impeded tumorigenesis and encouraged CD8⁺T cell infiltration, but these tumor-suppressive effects were rescued by S100A2 overexpression. This research suggests that E2F7 targets S100A2 to repress the activity of CD8⁺T cells in LUAD by modulating glutamine metabolism, highlighting the potential of targeting the E2F7/S100A2 axis or glutamine metabolic pathways to diminish immune evasion and enhance treatment efficacy in LUAD patients. KEY MESSAGES: S100A2 is upregulated in LUAD and inversely links to CD8⁺T cell infiltration. Enhanced S100A2 expression could manipulate glutamine metabolism. Enhanced S100A2 expression could dampen the cytotoxicity of CD8⁺T cells. S100A2 is transcriptionally activated by E2F7. Targeting E2F7/S100A2 axis may diminish LUAD immune evasion.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"31"},"PeriodicalIF":4.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146004900","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: GATA1 controls metadherin transcription to promote oxidative stress-induced podocyte injury.","authors":"Yihua Chen, Wenting Wu, Liyuan Zhao, Lingyu Shen, Danping Tao, Yunyi Liang, Xiaohong Zheng, Zerong Zheng, Congwei Luo, Fenfen Peng, Haibo Long, Xiaowen Chen","doi":"10.1007/s00109-026-02642-4","DOIUrl":"https://doi.org/10.1007/s00109-026-02642-4","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"30"},"PeriodicalIF":4.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000328","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":"cGAS-STING signaling pathway in MASLD and liver fibrosis.","authors":"Yang Xiao, Yufang Ma, Can Gan, Zhiyin Huang, Jinhang Gao","doi":"10.1007/s00109-025-02612-2","DOIUrl":"10.1007/s00109-025-02612-2","url":null,"abstract":"<p><p>In metabolic dysfunction-associated steatotic liver disease (MASLD), lipid accumulation and inflammatory stimulation lead to the release of damage-associated molecular patterns, thereby inducing the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. The cGAS-STING signaling pathway in the liver is primarily activated in Kupffer cells/macrophages, hepatic stellate cells, hepatocytes and liver sinusoidal endothelial cells. Emerging evidence also reveals that the cGAS-STING signaling pathway contributes to liver cell fate changes in MASLD. Herein, this review summarizes the role of the cGAS-STING signaling pathway in liver cells and its effect on cell fate in the context of MASLD and liver fibrosis. Therapeutic agents targeting the cGAS-STING signaling pathway may shed light on the clinical treatment of MASLD and liver fibrosis.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"29"},"PeriodicalIF":4.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992958","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":"Longitudinal analysis in Mecp2-het female mice reveals atypical nociceptive behaviours.","authors":"Javier Cuitavi, Elena Martínez-Rodríguez, María Abellán-Álvaro, Marina Rodríguez-Agut, Moisés García-Arencibia, Mónica Santos, Lucía Hipólito, Anabel Forte, Carmen Agustín-Pavón, Jose V Torres-Pérez","doi":"10.1007/s00109-025-02628-8","DOIUrl":"10.1007/s00109-025-02628-8","url":null,"abstract":"<p><p>Rett Syndrome (RTT), a neurodevelopmental disorder predominantly affecting females, is characterised by evolving symptoms impacting motor and sensory domains. Herein, we present a study of longitudinal analyses, from 2- to 6-month of age, of Mecp2 heterozygous (Mecp2-het) female mice to comprehensively explore pain perception in RTT. Interestingly, we found a significant variability in the timing and progression of symptom onset among Mecp2-het females, with individuals classified as either early- or late-symptomatic based on the emergence of hallmark neurological features such as clasping and gait abnormalities. This variability pinpoints the heterogeneity of the disease model and highlights the need to stratify Mecp2-het females by symptom onset in future studies to account for the diverse trajectories of disease progression. Additionally, our results reveal a shift from presymptomatic hypersensitivity in the von Frey test to apparent hyposensitivity, intricately linked with the onset of motor symptoms. Further, we found decreased neuronal activation in 6-month-old Mecp2-het females after the hot plate test in the periaqueductal grey, as measured by cFos expression, which does not happen with younger presymptomatic Mecp2-het females. Similarly, there is a lower expression of cannabinoid receptor 1 (CB1) in this area when compared to wild-type siblings. Taken together, our results suggest that both motor impairment and a possible dysregulation of endogenous analgesia might contribute to aberrant sensitivity in Mecp2-het mice. Our study emphasises the presymptomatic phase as crucial for understanding sensory abnormalities in Mecp2-het mice and highlights the challenges in identifying pain in RTT patients. KEY MESSAGES: Mecp2-het mice show early hypersensitivity to stimuli that shifts with age. Classification of Mecp2-het mice by symptom onset shows phenotypic variety. Mecp2-het mice show lower PAG activity when facing a thermal stimulus. Mecp2-het mice show decreased activity and CB1 receptor levels in the PAG.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"28"},"PeriodicalIF":4.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961226","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":"Measuring Neural Factor X Pathway Activity in Rodent Glioma Cell Culture and Brain Slices.","authors":"Valery Golderman, Shany Guly Gofrit, Maya Schiller, Joab Chapman, Efrat Shavit-Stein","doi":"10.1007/s00109-025-02610-4","DOIUrl":"10.1007/s00109-025-02610-4","url":null,"abstract":"<p><p>Coagulation factor X (FX) plays a significant role in neuroinflammation and is considered a promising target for therapeutic intervention. However, because activated FX (FXa) levels in neural tissues are expected to be significantly lower than in plasma, a more sensitive, direct, and specific method is required for accurate detection. To measure FXa activity with high sensitivity, we used a fluorogenic substrate in combination with a panel of specific inhibitors to prevent nonspecific protease activity that potentially cleaves the substrate, initially validated in human normal and FX-deficient plasma. This approach allowed selective quantification of FXa activity in neural samples. To further characterize the FX pathway, we applied a FXa inhibitor (apixaban), a FX activator (Russell's viper venom X, RVVX), and commercially available FX and FXa to mouse brain slices and to glioma cell lines derived from human, rat, and mouse. FXa activity significantly increased following RVVX application in human plasma and mouse brain and was inhibited in a calcium-dependent manner in human plasma. In the mouse brain, apixaban inhibited only the FXa activity secreted from the slice rather than the slice-associated activity. In glioma cell lines, RVVX application increased cell-bound FXa activity, which was not inhibited by apixaban, while the activity secreted into the medium was elevated and inhibited by apixaban. Exposure to lipopolysaccharide reduced RVVX-induced FXa activity while increasing the thrombin activity in glioma cell lines from mice and rats, respectively. We developed a specific method of measuring basal FXa activity and induced from FX by RVVX, in plasma and secreted from brain slices and astrocyte tumor cells. The results were obtained in tissue with defined experimental conditions, pharmacologically differentiated tools, and biological validation as assessed by thrombin activity measurement. FXa activity in neural tissue is tightly regulated and undetectable without an FX activator. KEY MESSAGES: We developed a sensitive method using fluorescence substrate to measure the fine changes in FXa activity in neural tissue. Brain slice associated FXa activity differs from secreted activity in its response to activators and inhibitors, suggesting the complexity of FXa activity regulation in neural tissue. Specific set of conditions is needed to detect FXa activity in neural tissue.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"27"},"PeriodicalIF":4.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961215","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 ApoA5-Cidec axis: keeping fibrosis and MASLD at bay.","authors":"Rita Sharma, Alexia Tasoula, Vishva M Sharma","doi":"10.1007/s00109-025-02634-w","DOIUrl":"10.1007/s00109-025-02634-w","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"26"},"PeriodicalIF":4.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947182","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":"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/s00109-025-02630-0","DOIUrl":"10.1007/s00109-025-02630-0","url":null,"abstract":"<p><p>Alveolar epithelial cell (AEC) senescence is a crucial driver of pulmonary fibrosis (PF). Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid through the cytochrome P450 cyclooxygenase (CYP) pathway. We have reported that EETs inhibit AEC senescence, alleviating bleomycin (BLM)-induced PF in mice. However, EETs have a short half-life in vivo and are rapidly degraded to low-active end-product diols by soluble epoxide hydrolase (sEH). We observed a significant increase in sEH expression in senescent AECs, but the underlying mechanism remains unclear. In this study, we found that inhibition of sEH significantly attenuated senescence in AECs and lung senescence in premature aging mice. Mechanistically, bioinformatics results showed that the spleen focus forming virus proviral integration oncogene (Spi1) might be a key transcription factor upstream of sEH in AECs. ChIP assay showed that Spi1 could bind to the sEH promoter. Knockout of Spi1 in AECs mediated by lentivirus significantly reduced BLM-induced sEH expression and AEC senescence, while overexpression of Spi1 had the opposite effect. Furthermore, specific silencing of Spi1 in AECs significantly inhibited BLM-induced PF in mice. Taken together, these findings provide new ideas for the treatment of PF by targeting Spi1 to improve AEC senescence. KEY MESSAGES: Spi1 is a key transcription factor upstream of sEH in AECs. Inhibition of Spi1 significantly attenuated AEC senescence. Inhibition of Spi1 alleviated pulmonary fibrosis in aging mice.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"25"},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145914643","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":"Exploring the pathogenesis of NAFLD: a study of the correlation of gut microbes and metabolites in humanized mouse gut microbiota.","authors":"Yuanzhi Cheng, Yun Yang, Yaxi Guo, Yang Shi, Jianghao Feng, Xiaoliang Jiang, Zhiwei Yang, Hua Zhu, Xing Liu","doi":"10.1007/s00109-025-02622-0","DOIUrl":"10.1007/s00109-025-02622-0","url":null,"abstract":"<p><p>There is mounting scientific evidence indicating a robust association between gut microbiota and nonalcoholic fatty liver disease (NAFLD). Exposure to commensal microbiota in germ-free mice has a significant impact on the regulatory mechanisms of gut genes, in contrast to those conventionally raised. In this study, we have successfully inoculated the gut microbiota from healthy individuals and NAFLD patients into germ-free mice, with the objective of developing a humanized mouse model that accurately replicates the gut microenvironment of NAFLD patients. Changes in blood composition and liver pathology in these mice were systematically measured. Furthermore, we have conducted a detailed analysis of the variations in fecal microbiota and differential metabolites in the blood composition. Our findings indicate a high degree of similarity in disease characteristics between mice colonized with microbiota and humans suffering from NAFLD. Notably, we have observed a strong correlation between alterations in serum differential metabolites and gut microbiota in these mice. KEY MESSAGES: A humanized NFALD mouse model was established based on sterile mice. In microbiota-colonized mice and humans with NAFLD, disease characteristics showed a high degree of similarity. There was a strong association between changes in serum differential metabolites and gut microbiota in mice colonized by intestinal microbiota.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"24"},"PeriodicalIF":4.2,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145914648","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}