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

{"title":"Tyrosine hydroxylase as a therapeutic target: insights from adrenergic nerve and TNBC cell interactions.","authors":"Yichen Luo, Yanhong Han, Huilong Nie, Minghao Feng, Cuiting Wei, Xiuling Ma, Kefeng Li, Zhuangzhuang Zhang, Guangxue Wang, Wenjun Pan, Xueyang Li, Liutong Yi, De-Yun Wang, Xian-Tao Zeng, Yongkang Qiao, Yan Yan, Yujing Lin","doi":"10.1007/s00109-026-02657-x","DOIUrl":"10.1007/s00109-026-02657-x","url":null,"abstract":"<p><p>The sympathetic adrenergic nerves (SAN) play a significant role in the malignant transformation of breast cancer cells through the activity of norepinephrine (NE). However, the role of tyrosine hydroxylase (TH), a key enzyme of the NE synthesis, in the interaction between the SAN and triple-negative breast cancer (TNBC) cells has not been sufficiently explored, and whether TH can be a therapeutic target for TNBC has not been reported. TH expression in TNBC was examined by analyzing data from an online database and immunohistochemical analysis of our clinical samples. Cell proliferation and drug sensitivity were assessed upon coculture with fluorescently labeled cells using IncuCyte. Changes in the expression of DNA damage and apoptosis-associated proteins were assessed by western blotting. TH expression and NE synthesis in PC12 cells after their coculture with TNBC cells were measured by RT-qPCR, immunofluorescence, and ELISA. RNA sequencing was conducted on the cells before and after coculture. TH expression was relatively high in TNBC tumor tissues and closely associated with prognosis. SAN promoted TNBC cell proliferation through NE and reduced TNBC cell sensitivity to chemotherapeutic agents. Additionally, tumor cells induced TH expression in PC12 cells through nerve growth factor (NGF) secretion. Knocking down TH and using TH inhibitors effectively reversed the proliferation-promoting and drug sensitivity-reducing effects of SAN in TNBC cells. TH may be a central molecule in the positive feedback loop between TNBC cells and SAN. TH is a potential prognostic biomarker and can also serve as a therapeutic target for TNBC. KEY MESSAGES: The overexpression of the sympathetic nerve biomarker tyrosine hydroxylase (TH) in triple-negative breast cancer (TNBC) is an indicator for clinical staging, prognosis, and targeted therapy. There is a feedback loop where TH in nerves produces NE, worsening TNBC and reducing chemotherapy effectiveness. TNBC cell then increases TH expression, further boosting NE production. Furthermore, blocking the activity of TH could effectively inhibit this phenotype.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489326","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":"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/s00109-026-02660-2","DOIUrl":"10.1007/s00109-026-02660-2","url":null,"abstract":"<p><p>Under diverse stimuli in the tumor microenvironment, tumor-associated macrophages (TAMs) are susceptible to polarize toward an immunosuppressive phenotype. Reprogramming TAMs is a promising strategy for cancer immunotherapy. As a downstream molecule of G protein-coupled receptors, the alpha subunit of the stimulatory G protein (Gsα) plays an indispensable role in the transduction of extracellular signals to intracellular signals. However, whether Gsα is responsible for the reprogramming and polarization of TAMs is largely unknown. Here, we demonstrate that Gsα deficiency in TAMs accelerates tumor growth and metastasis in B16 and MC38 tumor cells. Further investigations revealed that Gsα upregulates the expression of CD86, CCR5, Il1b and Nos2 and inhibits CD206 and Il10 expression, which facilitates the recruitment and antitumoral activity of TAMs and contributes to the increased effector activity of CD8⁺ T cells. Mechanistically, Gsα promotes the proinflammatory M1-like polarization of TAMs by increasing the phosphorylation of ERK, p38 and JNK in the MAPK signaling pathway. In summary, our study indicates that Gsα-deficient TAMs exhibit protumoral activity via the MAPK pathway, suggesting a novel potential target for cancer immunotherapy based on TAMs reprogramming. KEY MESSAGES: Deficiency of Gsα in TAMs accelerates tumor growth and metastasis in B16 and MC38 tumor models in vivo and in vitro. Further investigations reveal that Gsα upregulates expression of CD86, CCR5, Il1b and Nos2, and inhibits CD206 and Il10 expression, which facilitates antitumoral activity of TAMs. Mechanistically, Gsα promotes M1 polarization of TAMs via upregulating phosphorylation of ERK, p38 and JNK in MAPK signaling pathway.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489298","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":"Targeting EFEMP1 enhances chondrogenesis and inhibits hypertrophic differentiation in a spontaneous osteoarthritis mouse model.","authors":"Yuhan Chang, Pei-Heng Jiang, Yung-Heng Hsu, Yu-Chih Lin, Chih-Chien Hu, Yi-Zhen Li, Steve Wen-Neng Ueng, Mei-Feng Chen","doi":"10.1007/s00109-026-02656-y","DOIUrl":"10.1007/s00109-026-02656-y","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degradation. EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) has been implicated in cartilage development and OA pathogenesis, as its expression inhibits chondrogenesis and declines during mesenchymal stem cell differentiation. This study was aimed at investigating the role of EFEMP1 in cartilage regulation and evaluating the therapeutic potential of EFEMP1 inhibition in OA. EFEMP1 knockdown mediated by small interfering RNA (siRNA) was performed in human chondrocyte and mouse preosteoblast cultures. In chondrocytes, EFEMP1 knockdown downregulated hypertrophic markers (MMP-13, COL10A1) and upregulated SOX9 and aggrecan. Furthermore, phosphokinase analysis revealed increased activities of p70S6K, β-catenin, and HSP60. In osteoblasts, EFEMP1 knockdown reduced RUNX2 expression, calcification, and ALP activity. In vivo, STR/ort spontaneous OA mice were treated with EFEMP1-neutralizing antibody to assess cartilage preservation and cytokine modulation. As a result, EFEMP1 antibody treatment increased matrix-producing chondrocytes, improved cartilage integrity, and lowered OARSI scores. It also enhanced SOX9 and COL2A1 expression while suppressing COL10A1. Although no significant changes were observed in subchondral bone parameters, cytokine analysis revealed a chondroprotective effect in the EFEMP1 antibody-treated group. In conclusion, EFEMP1 inhibition promotes chondrogenesis, suppresses chondrocyte hypertrophy, and modulates inflammatory signaling, contributing to cartilage preservation and attenuation of OA progression. These findings identify EFEMP1 as a potential therapeutic target for OA. KEY MESSAGES: EFEMP1 inhibition promotes chondrogenesis and reduces hypertrophic markers, supporting cartilage maintenance and delaying OA progression. EFEMP1 antibody treatment enhances chondroprotective cytokines while suppressing inflammatory cytokines, contributing to joint preservation in OA mice. Despite its beneficial effects on cartilage, EFEMP1 inhibition does not significantly alter subchondral bone parameters, highlighting its selective role in OA pathology.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12999771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483144","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":"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/s00109-026-02653-1","DOIUrl":"10.1007/s00109-026-02653-1","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease and atherosclerosis may share a common pathogenesis involving chronic IL-1β-induced inflammation. We aimed to evaluate the efficacy of diacerein, an IL-1 pathway inhibitor, in improving liver fibrosis, steatosis, and atherosclerosis in apolipoprotein E-knockout (apoE k/o) mice. ApoE k/o mice fed a high-fat diet (HFD) were divided into three groups based on diacerein dosage. Liver fat accumulation and fibrosis severity were compared across groups, along with changes in the expression of genes related to lipid metabolism and fibrosis. Atherosclerotic burden in the aorta was evaluated via en face analysis, and the related signaling pathway was verified in vitro. Diacerein treatment reduced the amount of collagen fibers and fat accumulation in the liver in a dose-dependent manner as well as fibrosis-related gene expression. Atherosclerotic plaque burden in the aorta showed a decreasing trend with diacerein treatment, accompanied by reduced expression of pro-inflammatory cytokines, including TNF-α. Diacerein treatment ameliorated liver steatosis/fibrosis and showed beneficial effects on atherosclerosis-related mechanisms in HFD-fed apoE k/o mice. Given its dual anti-inflammatory and anti-fibrotic actions, diacerein represents a promising therapeutic candidate for metabolic disorders characterized by chronic inflammation. KEY MESSAGES: We analyzed the effects of diacerein on liver fibrosis, steatosis, and atherosclerosis in apolipoprotein E knockout (apoE k/o) mice. Diacerein reduced fat accumulation in the liver and collagen fibers in the liver. It decreased the expression of genes related to fibrosis and the burden of atherosclerotic plaque in the aorta. The expression of pro-inflammatory cytokines was reduced. Treatment of apoE knockout mice fed an HFD with diacerein effectively ameliorated liver steatosis/fibrosis and atherosclerosis.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12979423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439117","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":"Metformin sensitizes endometriosis to medroxyprogesterone acetate treatment through MIG-6 mediated signaling.","authors":"Guanwen Gao, Lvfang Duan, Fanyue Zhu, Wenkui Dai, Lina Geng, Degao Liu, Jinju Lin, Huashan Zhao, Yunfei Wang, Changzhong Li","doi":"10.1007/s00109-026-02655-z","DOIUrl":"10.1007/s00109-026-02655-z","url":null,"abstract":"<p><p>This study evaluates the synergistic therapeutic effect of metformin (MET) combined with medroxyprogesterone acetate (MPA) on endometriosis (EM) and investigates the involvement of the steroid receptor coactivator-1 (SRC-1) and mitogen-inducible gene 6 (MIG-6). Immunohistochemical analysis revealed significantly decreased SRC-1, progesterone receptor (PGR), and MIG-6 protein expression in human ectopic EM lesions compared to normal eutopic endometrium. In an EM mouse model, the combination of metformin (MET) and MPA resulted in the greatest reduction of ectopic lesion size and weight compared to either treatment alone. This combination therapy also uniquely increased serum Eotaxin and decreased interleukin-12p40 levels. Transcriptome analysis demonstrated specific enrichment of immune activation pathways only in the combination treatment group. In vitro, using the human endometriosis epithelial cell line 12Z, the MET and MPA combination significantly suppressed cell proliferation and migration, concomitant with an upregulation of SRC-1, PGR, and MIG-6 messenger RNA expression. We conclude that MET enhances the therapeutic efficacy of MPA against EM. This effect may be mediated through MIG-6 signaling and involves the upregulation of SRC-1, inhibiting ectopic cell proliferation and migration, and inhibiting endometriotic lesion progression, representing a novel strategy to overcome progesterone resistance. KEY MESSAGES: SRC-1, MIG-6, and PGR are downregulated in human endometriotic lesions. MET and MPA act cooperatively to suppress lesion growth in a murine model. Combination therapy increases Eotaxin levels while decreasing IL-12p40 in mice. MET and MPA activate immune surveillance pathways within lesions. MET and MPA synergistically inhibit endometriotic cell growth and migration.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629806","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":"Genetic analysis and reporting from whole-exome sequencing data in 1052 patients with intellectual disability.","authors":"Xin Pan, Guanhua Qian, Li Liu, Xu Zhang, Yang Yang, Qingyun Zhang, Xianglan Tang, Nanyan Yang, Lijie Dong, Hong Yao, Xiaojing Dong, Bo Tan","doi":"10.1007/s00109-026-02652-2","DOIUrl":"10.1007/s00109-026-02652-2","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Intellectual disability (ID) is a genetically heterogeneous neurodevelopmental disorder, with etiological diagnosis remaining challenging due to clinical phenotypes and genetic diversity. To investigate the diagnostic value of whole exome sequencing (WES) combined with copy number variation (CNV) analysis in unexplained ID through a large cohort analysis, and to analyze the genetic etiology of intellectual disability. Performed WES on 1052 individuals with unexplained ID, analyzing single nucleotide variants (SNVs), small insertions/deletions (InDels), and CNVs. Variants were classified as pathogenic or likely pathogenic based on clinical guidelines. Four hundred eighty-five pathogenic or likely pathogenic variants that could explain the clinical indication were identified in 458 individuals, with an overall diagnostic rate of 43.54% (458/1052). Three hundred thirty-three SNVs were detected, distributed in 178 genes, of which 222 cases were novel. Inheritance pattern analysis showed that autosomal dominant inheritance was the most prevalent (242/333, 72.67%), followed by recessive inheritance (41/333, 12.31%) and sex-linked inheritance (50/333, 15.02%), which aligns with the established role of new dominant variants in developmental disorders. By CNV analysis, we further identified 152 structural variant events with sizes ranging from 103.54 bp to 67.34 Mbp. WES with CNV analysis significantly improves molecular diagnosis in ID, particularly in cases of unclear etiology. This integrated approach elucidates diverse variantal mechanisms and enhances genotype-phenotype correlations, supporting clinical management and genetic counseling. WES combined with CNV analysis provides a powerful and economical approach for ID diagnosis. This study offers valuable insights for precision diagnosis and genetic counseling in Chinese ID populations. KEY MESSAGES: 1. Whole-Exome Sequencing (WES) Significantly Enhances Diagnostic Yield in Intellectual Disability (ID) 2. WES analysis of 1052 Chinese ID patients achieved a diagnostic yield of 43.54%, surpassing chromosomal microarray analysis (CMA, 15-20%) and aligning with prior WES studies in neurodevelopmental disorders (NDDs). By integrating detection of single nucleotide variants (SNVs), insertions/deletions (Indels), and exon-level copy number variations (CNVs), WES overcomes limitations of traditional methods, particularly for patients with complex phenotypes or genetic heterogeneity. 3. SNVs Dominate the Genetic Etiology of ID 4. SNVs accounted for 68.7% (333/485) of pathogenic or likely pathogenic variants, reinforcing their critical role in ID pathogenesis. 5. CNV Analysis from WES Data Improves Diagnostic Efficiency 6. A total of 152 pathogenic or likely pathogenic CNVs (31.3% of all variants) were identified, including 150 patients diagnosed solely through CNV analysis, increasing the overall diagnostic yield by 14.3%. Advanced algorithms (e.g., XHMM, HMZDelFinder) enabled precise detection of small","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147322596","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":"Piezo1/PI3K-induced autophagy dysregulation in PDLSCs under mechanical stress during root resorption.","authors":"Kuan Yang, Xiaoxi Lu, Qiang Zhang, Yujiang Chen, Xiao Yuan","doi":"10.1007/s00109-026-02647-z","DOIUrl":"10.1007/s00109-026-02647-z","url":null,"abstract":"<p><p>This study aimed to clarify the mechanobiological mechanisms of physiological root resorption in deciduous teeth, focusing specifically on how mechanical stress influences autophagy in periodontal ligament stem cells (PDLSCs) via the Piezo1 ion channel. We established a unilateral occlusal loading model in mice to simulate physiological mechanical stress, while in vitro studies utilized PDLSCs isolated from deciduous teeth at different resorption stages. Techniques included immunofluorescence staining for autophagy markers, Western blot analysis, Piezo1-specific pharmacological modulation, and transcriptome sequencing. Conditional Piezo1 knockout mice were generated to validate the mechanotransduction pathway. Our findings revealed distinct stage-dependent patterns in PDLSC behavior: early resorption stage (S-stage) cells maintained high autophagic activity with low IL-1β secretion, while mid-resorption stage (M-stage) cells showed Piezo1 upregulation and autophagy suppression. Mechanical stress was shown to inhibit autophagy through Piezo1-mediated activation of the PI3K/AKT pathway. Transgenic mouse models confirmed Piezo1's essential role in mediating mechanical stress responses in periodontal tissue. The study establishes Piezo1 as a critical mechanotransducer that coordinates stage-specific autophagy regulation in PDLSCs through the PI3K/AKT signaling pathway. These findings suggest that controlled modulation of mechanical forces or Piezo1 activity could offer new therapeutic strategies for managing deciduous tooth exfoliation. KEY MESSAGES: Mechanical stress inhibits PDLSC autophagy via Piezo1/PI3K/AKT pathway. Piezo1 is key for mechanosensing in periodontal tissue remodeling. Targeting mechano-autophagy may regulate deciduous root resorption.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147274256","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":"Lipids in kidney diseases: from systemic imbalance to intrarenal alterations of cellular lipid metabolism in rare and common kidney diseases.","authors":"Carola Garavaglia, Alice Ossoli, Monica Gomaraschi","doi":"10.1007/s00109-026-02654-0","DOIUrl":"10.1007/s00109-026-02654-0","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is expected to be the fifth cause of global mortality by 2040. Modifiable and non-modifiable risk factors for CKD range from metabolic conditions, such as diabetes or obesity, to genetic defects. Regardless of the triggering factor, irreversible injury and loss of kidney cells result in the decline of kidney function. Renal damage often occurs through common signaling pathways promoting inflammation, oxidative stress, organelle dysfunction, complement activation, apoptosis, and fibrogenesis. Lipotoxicity is emerging as a key player in CKD of both metabolic and non-metabolic origin. Here, we provide an overview of the mechanisms beyond renal lipid accumulation in CKD, ranging from systemic imbalance of lipid/lipoprotein metabolism to alterations of cell lipid uptake, synthesis, and disposal. Moreover, the impact of lipid accumulation in glomerular and tubular cells is addressed. Several lipid species were shown to accumulate in renal cells, from cholesterol and fatty acids to sphingolipids; they can affect cell viability and function not only as structural components of biological membranes or energetic substrates but also as bioactive molecules able to modulate multiple signaling pathways. The possible role of established and novel approaches to correct systemic or local lipid imbalance in the management of CKD is discussed.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"46"},"PeriodicalIF":4.2,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230481","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":"Anti-myeloma activity of the CXCR4 antagonist WZ811.","authors":"Danka Cholujova, Nikoleta Csicsatkova, Zuzana Valuskova, Katarina Suroviakova, Maria Elisabeth Marinkovicova, Anna Strizova, Jan Sedlak, Jana Jakubikova","doi":"10.1007/s00109-026-02650-4","DOIUrl":"10.1007/s00109-026-02650-4","url":null,"abstract":"<p><p>The CXCR4-CXCL12 axis is crucial for the interaction between malignant plasma cells (PC) and their microenvironment in multiple myeloma (MM). Here, we show that CXCR4 expression is upregulated in MM cell lines and PCs during both premalignant and active stages of MM, compared to normal PCs from healthy donors. The CXCR4 antagonist WZ811 reduced the viability of MM PCs and cell lines, while tumor microenvironment cells from both MM patients and healthy donors exhibited significant resistance. In vivo, WZ811 significantly reduced tumor burden and improved survival. WZ811-mediated MM cell death involved disruption of mitochondrial transmembrane potential, externalization of transmembrane phosphatidylserine, activation of caspases, increased levels of autophagic proteins, and an increase in G₀/G₁ phase of the cell cycle. WZ811 also eliminated the MM stem cell-like side population, though slight resistance was observed with stromal cells. Additionally, WZ811 increased levels of CXCL12 and extracellular matrix molecules collagen IV and laminin in MM cells. Combining WZ811 with anti-MM agents showed synergism with doxorubicin, dexamethasone, bortezomib, lenalidomide, and pomalidomide, while antagonism was observed with carfilzomib, supporting the clinical assessment of WZ811 in MM.  KEY MESSAGES: WZ811 reduced the viability of myeloma primary cells and cell lines. WZ811 reduced tumor burden and improved survival in vivo xenograft model. WZ811 mechanisms involved apoptotic and autophagic cell death. WZ811 eliminated the MM stem cell-like side population. WZ811 synergized with DOX, DEX, BTZ, LEN, and POM.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"45"},"PeriodicalIF":4.2,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12913330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215567","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":"TFR2 p.A75V mutation aggravates liver iron overload in alcoholic liver disease via ERK pathway.","authors":"Chao Xie, Yingying Liu, Xiaofan Wang, Long Huang, Xiaoming Wang, Wei Zhang, Lina Wu, Tianhui Liu, Ping Wang, Lin Liu, Xu Fan, Jidong Jia, Xiaojuan Ou, Anjian Xu, Min Cong","doi":"10.1007/s00109-026-02640-6","DOIUrl":"10.1007/s00109-026-02640-6","url":null,"abstract":"<p><p>Liver iron overload, a contributing factor to liver damage, is frequently observed in advanced alcoholic liver disease (ALD). Genetic factors may influence the progression of ALD. This study explored the involvement of hemochromatosis-related genes in liver iron deposition among ALD patients. Clinical data from 97 ALD patients revealed that those with liver iron overload had worse liver function and prognosis. Among 43 patients who underwent exon sequencing of the HFE, HJV, HAMP, TFR2, and SLC40A1 genes, the TFR2 p.A75V mutation emerged as a potential contributor to iron overload. To further investigate, we developed a novel mouse model of ALD with liver iron overload. Administration of recombinant AAV carrying the wild-type TFR2 gene significantly reduced iron deposition in hepatocytes, whereas the TFR2 p.A75V mutation did not alleviate hepatic iron overload. This mutation impairs HAMP induction by disrupting the ERK pathway, likely due to abnormal cytoplasmic localization of the TFR2 protein. In conclusion, the TFR2 p.A75V mutation in ALD may decrease hepatocyte sensitivity to iron stimulation by inhibiting HAMP expression via the ERK pathway, thereby exacerbating iron overload both in vivo and in vitro. KEY MESSAGES: The study identifies the TFR2 p.A75V mutation as a key genetic factor worsening liver iron overload in ALD patients, linked to poorer liver function and prognosis. A novel ALD mouse model with iron overload demonstrates that the TFR2 p.A75V mutation impairs iron regulation. TFR2 p.A75V mutant disturbs the ERK pathway in HAMP induction and causes abnormal cytoplasmic localization of the TFR2 Protein.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"44"},"PeriodicalIF":4.2,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169218","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}