Molecular biomedicine最新文献

{"title":"Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets.","authors":"Yue Pan, Wan-Hong Li, Wei Zhang, Wan-Jing Ma, Hui Sun","doi":"10.1186/s43556-026-00599-x","DOIUrl":"10.1186/s43556-026-00599-x","url":null,"abstract":"<p><p>Cardiovascular disease progression is shaped by a close interaction between metabolic adaptation and inflammatory signaling. In injured cardiac and vascular tissues, ischemia, pressure overload, lipid stress and metabolic excess reshape how cardiomyocytes, endothelial cells, immune cells and fibroblasts sense damage and communicate with their microenvironment. Cardiovascular inflammation follows a staged tissue response, from danger-signal sensing and nuclear factor-κB-related priming to inflammasome activation, cytokine amplification, leukocyte recruitment, efferocytosis and chronic remodeling. Metabolic reprogramming shapes this sequence by altering substrate use, redox control, biosynthetic routing and metabolite signaling. A major challenge is that glycolysis, fatty acid oxidation and amino-acid metabolism do not carry fixed biological meanings; their effects depend on the cell type, measurement layer and disease phase in which they occur. This review examines metabolism-inflammation crosstalk in cardiovascular disease by linking core inflammatory pathways with metabolic sensors, immune-cell metabolic reprogramming and signaling metabolites, then comparing disease-specific mechanisms in myocardial infarction/ischemia-reperfusion injury, heart failure, atherosclerosis, hypertrophic remodeling and myocardial fibrosis. We emphasize how apparently similar metabolic shifts can represent adaptive repair, inflammatory amplification or maladaptive remodeling in different compartments. The therapeutic discussion separates pathway activity from targetability and uses anti-inflammatory trials and metabolic interventions to define when patient selection, pathway engagement and safety considerations support targeted treatment.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042444","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":"Craniofacial development: genetics, signaling pathways, teratogenic mechanisms, and clinal significance.","authors":"Xinli Lv, Juan Du","doi":"10.1186/s43556-026-00574-6","DOIUrl":"10.1186/s43556-026-00574-6","url":null,"abstract":"<p><p>Craniofacial development is a highly coordinated and stage-specific process involving neural crest cell migration, proliferation, differentiation, and epithelial-mesenchymal transition. Genetic mutations, signaling pathway abnormalities, and exposure to environmental teratogens can disrupt normal development. These anomalies can lead to cleft palate, craniosynostosis, and other common congenital craniofacial malformations. Although significant progress has been made in understanding craniofacial development in recent years, the systematic integration of these factors remains limited. Here, we provide a comprehensive review of the cellular and molecular mechanisms underlying normal craniofacial development, focusing on the coordinated regulation of cranial neural crest cells by transcription factors, signaling pathways and epigenetic programs. We further summarize major pathogenic mechanisms implicated in craniofacial disorders. Additionally, the teratogenic mechanisms underlying maternal endogenous and external environmental exposures are explored, with particular emphasis on their interactions with genetic factors in reshaping developmental trajectories. We emphasize the central role of gene-environmental interactions in craniofacial pathogenesis by integrating evidence from developmental biology, multi-omics studies and clinical studies. Subsequently, we outline current clinical diagnostic techniques and management strategies for craniofacial malformations, pointing out the existing challenges and future directions. This review establishes a comprehensive framework linking gene regulation, metabolic environment, and clinical implications. It is expected to facilitate deeper insights into disease mechanisms and promoting the translation of basic research findings into clinical diagnosis, prevention, and management of craniofacial disorders.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042494","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 DCBLD2 super-enhancer drives colorectal cancer progression through FOSL2/JUND-mediated activation of the CD146/AKT/TNFRSF6B pathway.","authors":"Tong Wu, Lan Shao, Xin Hu, Hongjuan He, Lu Chen, Meiqi Feng, Chengjin Qi, Ziwen Wang, Haoran Yu, Boshu Ji, Yijia Cao, Yan Zhang, Qiong Wu","doi":"10.1186/s43556-026-00592-4","DOIUrl":"10.1186/s43556-026-00592-4","url":null,"abstract":"<p><p>Super-enhancers are clusters of cis-regulatory elements that sustain the expression of cell-identity genes. Their aberrant activation or dysfunction constitutes a hallmark of malignant cellular transformation, which frequently rewires oncogenic transcriptional programs to support uncontrolled cell proliferation and metastatic potential. However, the functions and epigenetic regulation mechanisms of colorectal cancer specific super-enhancers remain poorly understood, and few studies have focused on dissecting how tumor enriched super-enhancers mediate downstream oncogenic signaling in CRC. By integrating multi-omics sequencing data, we identified a highly active super-enhancer in colorectal cancer, termed DCBLD2-SE. Through luciferase reporter assays, the SE3-2 subregion was identified as the minimal functional core of this super-enhancer. Mechanistic studies confirmed that transcription factors of the activator protein-1 family (FOSL2 and JUND) can bind directly to the SE3-2 cis-regulatory element, synergistically regulating local chromatin remodeling and strongly driving the upregulation of the target gene DCBLD2. Following knockout of the DCBLD2-SE core region, the malignant proliferative capacity of colorectal cancer cells decreased significantly, and the growth of xenograft tumors in vivo was markedly inhibited. Functionally, DCBLD2-SE facilitates tumor progression through a DCBLD2-dependent CD146/AKT/TNFRSF6B signaling axis. Clinically, high expression of DCBLD2 correlates with malignant metastasis and poor overall survival in patients with colorectal cancer. In summary, this study uncovers a previously undescribed DCBLD2-centered regulatory cascade that promotes colorectal cancer initiation and progression. DCBLD2-SE and its binding transcription factor activator protein-1 represent promising prognostic biomarkers and actionable therapeutic targets for colorectal cancer.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149032120","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":"Fine-tuning the lysine-arginine duet: a dietary approach to suppress tumor growth.","authors":"Ben-Chi Zhao, Xin-Yuan Zhao, Wen-Xiu Li, Xiao Lan, Xiao-Ming Huang, Hao Feng, An-Qi Li, Run-Lu Shi, Hui-Lin Li, Xi Xie, Guo-Hui Wan, Ren-Jie Jiao, Di Chen, Jian-Sheng Kang, Qiao-Ping Wang","doi":"10.1186/s43556-026-00588-0","DOIUrl":"10.1186/s43556-026-00588-0","url":null,"abstract":"<p><p>While dietary therapies targeting individual amino acids in cancer show promise in modulating tumor metabolism, the issue of nutrient competition between tumors and the immune system remains unresolved. The current approaches face significant challenges, particularly in the context of metabolic adaptability and immune responses. Here, we demonstrate that the combined modulation of lysine (Lys) and arginine (Arg) balances tumor suppression and host fitness. Using a cross-species approach combining Drosophila and mouse models, we define a narrow therapeutic window for Lys and Arg. A balanced combination (0.5% Lys/0.5% Arg) reduces tumor burden, extends survival, and preserves host fitness in tumor-bearing mice, whereas an imbalanced formulation (0.25% Lys/1% Arg, LLHA) paradoxically accelerates tumor progression. Single-cell RNA sequencing revealed that LLHA was associated with increased B cells, M1-annotated macrophages and reduced T cells, consistent with systemic immune remodeling that may favor tumor progression, accompanied by decreased Rps6 and Rps29 and increased Hba-a1 and Hbb-bt expression, suggesting alterations in mechanistic target of rapamycin (mTOR), hemoglobin, and ribosomal/translational pathways in immune cells. By defining biphasic thresholds and identifying optimal Lys/Arg combinations, this work provides a preclinical framework for investigating how balanced Lys/Arg modulation may influence tumor control and host fitness. This represents a step towards potential future synergy with immunotherapies, contingent upon further validation of immune dependency.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027139","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":"α1-Antitrypsin attenuates microglial NLR family pyrin domain containing 3 inflammasome activation via cannabinoid receptor 2 signaling to ameliorate α-synucleinopathy-related behavioral deficits.","authors":"Linjuan Feng, Hsuan Lo, Weipin Weng, Jiahao Zheng, Yixin Sun, Wei Lin, Xiaochun Chen, Yanping Wang, Xiaodong Pan","doi":"10.1186/s43556-026-00583-5","DOIUrl":"10.1186/s43556-026-00583-5","url":null,"abstract":"<p><p>α-Synucleinopathies are marked by persistent neuroinflammation and disabling non-motor symptoms involving nucleus accumbens (NAc) dysfunction, yet the neuroimmune mechanisms linking microglial activation to accumbal synaptic pathology remain poorly understood. Here, we identify α1-antitrypsin (AAT) as a previously unrecognized modulator of cannabinoid receptor 2 (CB2R)-associated signaling in α-syn pathology. An acute transcriptomic screen revealed prominent induction of the Serpina1 gene family, while primary-microglial and chronic AAV-α-syn experiments showed that Cnr2 deficiency amplified Serpina1/AAT responses, consistent with an insufficient compensatory reaction to persistent inflammation. Molecular docking, reciprocal co-immunoprecipitation, and surface plasmon resonance provided complementary evidence supporting an AAT-CB2R association under the respective assay conditions. Functionally, AAT reduced the α-syn-associated elevation of intracellular cAMP in an AM630-sensitive manner and attenuated ATP-evoked Ca²⁺ responses, calpain-1 activity, GSK-3β N-terminal cleavage, and NLRP3/caspase-1-related cytokine production; these effects were substantially diminished in Cnr2-deficient microglia. Calpeptin reproduced key molecular effects, implicating calpain-related proteolysis in this neuroimmune response. In vivo, intracerebroventricular AAT preserved NAc synaptic ultrastructure, ameliorated excitatory synaptic abnormalities in dopamine D2 receptor-expressing medium spiny neurons, and improved fear-memory retrieval, spontaneous alternation, and anxiety-like behavior, without affecting novel object recognition or motor performance. Several effects were attenuated under Cnr2-deficient conditions, although selected electrophysiological responses persisted. Our findings identify AAT-CB2R-linked signaling as a modulator of microglial inflammatory homeostasis and support the therapeutic potential of AAT for NLRP3-associated neuroinflammation and non-motor dysfunction in α-synucleinopathies.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013200","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":"Ovarian tumor domain-containing protein 1 deficiency attenuates metabolic dysfunction-associated steatotic liver disease by promoting the ubiquitination of HSP90α in hepatocytes.","authors":"Mei-Qin Huang, Si-Yi Wei, Meng-Zhe Li, Tian-Yu Chen, Shu-Qin Ou, Meng Gao, Feng Shi, Tao Zhang, Ying-Lan Liu, Meng-Zhuo Qin, Run-Lei Du, Qi Zhang, Bai-Qi Wang, Xiao-Dong Zhang","doi":"10.1186/s43556-026-00595-1","DOIUrl":"10.1186/s43556-026-00595-1","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, yet approved pharmacotherapies remain limited. The ovarian tumor domain-containing protein 1 (OTUD1) has been implicated in metabolic regulation, but its role in MASLD remains unclear. OTUD1 expression was significantly elevated in liver samples from patients with MASLD and in high-fat diet (HFD)-fed mice, a finding further supported by two independent Gene Expression Omnibus (GEO) cohorts (GSE24807 and GSE126848). Studies using systemic Otud1-knockout mice showed that Otud1 deficiency markedly alleviated insulin resistance and inflammation under HFD and high-fat, methionine-restricted, choline-deficient (HFMCD) diet conditions. To assess the hepatocyte-specific and therapeutic relevance of OTUD1, Otud1 was silenced in hepatocytes using AAV8-TBG-shOtud1, which significantly ameliorated HFMCD-induced steatohepatitis. Mechanistically, integrated interactome analyses identified heat shock protein 90α (HSP90α) as a direct substrate of OTUD1. OTUD1 bound to HSP90α and removed its K48-linked polyubiquitin chains at K283, thereby preventing its proteasomal degradation and enhancing its stability. This effect was required for OTUD1-driven lipid accumulation in hepatocytes, as the catalytically inactive OTUD1-C320S mutant failed to stabilize HSP90α or promote lipid deposition. Transcriptomic profiling further revealed that OTUD1 overexpression activated lipid metabolism and inflammatory pathways in OA/PA-treated LO2 cells. Together, these findings identify OTUD1 as a previously unrecognized driver of MASLD progression through the OTUD1-HSP90α axis and suggest that OTUD1 may serve as a potential therapeutic target for metabolic liver disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012931","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":"Stress-induced lipocalin 2 remodels the tumor microenvironment to exclude T cells.","authors":"Xinxiao Zhu, Jian Zhou, Fangfang Zhou","doi":"10.1186/s43556-026-00582-6","DOIUrl":"10.1186/s43556-026-00582-6","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002767","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":"CRISPR/dCas9-induced upregulation of endogenous apolipoprotein A1 and paraoxonase 1 genes reduces the aortic lipid deposits in apoE^-/- mice.","authors":"Laura Toma, Teodora Barbălată, Jessica Isabela Cătălina Hărătău, Gabriela Maria Sanda, Elena Valeria Fuior, Ioana Mădălina Fenyo, Loredan Ştefan Niculescu, Laura-Maria Dăian, Shlomo Sasson, Anca Volumnia Sima, Camelia Sorina Stancu","doi":"10.1186/s43556-026-00580-8","DOIUrl":"10.1186/s43556-026-00580-8","url":null,"abstract":"<p><p>High-density lipoproteins (HDL) are essential to alleviate the progression of atherosclerosis by mediating reverse-cholesterol transport, antioxidant and anti-inflammatory effects. We aimed to enhance the expression of endogenous HDL components, apolipoprotein A1 (APOA1) and antioxidant enzyme paraoxonase 1 (PON1), and to investigate their athero-protective effects. The CRISPR/dCas9 technology was used to activate the transcription of endogenous APOA1/PON1 in human hepatocytes (Huh7 line) and Apoa1/Pon1 in apoE^-/- mice. The expression of APOA1/PON1 genes was successfully upregulated in hepatocytes, and their proteins were secreted in the culture medium in the presence/absence of tumor necrosis factor-α (TNFα). APOA1-rich Huh7-derived conditioned medium exerted antioxidant and anti-inflammatory effects in TNFα-activated EA.hy926 endothelial cells. A single dose of the CRISPR/dCas9 plasmids i.v. injected in apoE^-/- mice increased the expression of hepatic Apoa1/Pon1 and their serum levels up to four weeks. FPLC analysis showed that increased serum APOA1 was distributed between HDL, LDL, and in lipid-free form. These mice also exhibited high levels of hepatic, gallbladder and feces cholesterol, in part due to the upregulation of hepatic scavenger receptor class-B1, cholesterol 7-alpha-hydroxylase, and ATP-binding cassette sub-family-G-member-8 transporter. In apoE^-/- mice with upregulated Apoa1/Pon1, no increased inflammatory stress or innate immune activation were detected, while lipid peroxides were decreased in PON1 mice. Of major interest, the area of aortic lipid deposits was halved in the treated mice. Our findings demonstrate the successful upregulation of endogenous Apoa1/Pon1 in apoE^-/- mice by using the CRISPR/dCas9 system, and highlight new mechanisms for APO1/PON1 anti-atherosclerotic action, explaining the reduction of aortic lipid deposits.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993054","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":"Induction of transferrin receptor 1-mediated ferroptosis by ultrasound-triggered microbubble destruction sensitizes glioblastoma to radiotherapy.","authors":"Ying He, Xunhu Dong, Xiaolu Lu, Qiong Zhu, Qingqing Miao, Zexuan Yan, Qingning Zhao, Hongying Chen, Min Qin, Yuehua Yi, Jiaqi Li, Dan Yang, Hanyun Zhang, Yali Xu, Mingliang Chen, Xiuwu Bian, Xing Hua","doi":"10.1186/s43556-026-00572-8","DOIUrl":"10.1186/s43556-026-00572-8","url":null,"abstract":"<p><p>Ultrasound-triggered microbubble destruction (UTMD), a non-invasive technique, has been proposed as a promising means of improving the efficacy of radiotherapy against glioblastoma (GBM); however, the underlying mechanisms remain to be fully clarified. Here, UTMD was shown to induce ferroptosis, an iron-dependent form of regulated cell death, in ionizing radiation (IR)-treated GL261 and 1016B cells, as evidenced by decreased cell viability, glutathione, and glutathione peroxidase 4 levels, and increased total reactive oxygen species (ROS), lipid ROS, iron/Fe²⁺, malondialdehyde contents, acyl-CoA synthetase long-chain family member 4 expression and cell death. Suppression of ferroptosis by ferrostatin-1 or deferoxamine abolished UTMD-induced radiosensitization in GBM cells, whereas blockade of apoptosis, autophagy, or necroptosis showed no significant effect. Conversely, induction of ferroptosis using erastin, RAS-selective lethal 3, and ferric ammonium citrate further promoted UTMD-mediated radiosensitivity of GBM cells. Mechanistically, UTMD markedly increased transferrin receptor 1 (TFR1) expression in IR-exposed GBM cells. TFR1 downregulation reversed UTMD-caused increase of intracellular Fe²⁺, subsequently inhibiting UTMD-induced ferroptosis and radiosensitivity of GBM cells, which were augmented by TFR1 overexpression. In GBM-bearing C57BL/6J and NOD-SCID mouse models, UTMD similarly upregulated TFR1 expression, triggered ferroptosis, and sensitized tumors to IR, and these effects were reversed by TFR1 knockdown. In conclusion, UTMD promoted the radiosensitivity of GBM partially by induction of TFR1-mediated ferroptosis, providing novel insights into the mechanism underlying UTMD-mediated radiosensitization.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002753","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":"Extracellular signal-regulated kinase 3 forms a nuclear complex with Aly/REF export factor and the splicing factor proline and glutamine rich to exacerbate pathological cardiac remodeling due to pressure overload.","authors":"Wen-Ying Zhou, Feng Wang, Shu-Yu Wang, Li-Guo Wang, Ai-Qun Chen, Haoyue Tang, Ya-Peng Chen, Huan Zhang, Xiao-Fei Gao, Juan Zhang, Shao-Liang Chen, Jun-Jie Zhang","doi":"10.1186/s43556-026-00563-9","DOIUrl":"10.1186/s43556-026-00563-9","url":null,"abstract":"<p><p>Pathological cardiac remodeling is a significant contributor to heart failure and mortality. Studies have demonstrated that extracellular signal regulated kinase 3 (ERK3) in cardiac fibroblasts aggravates pressure overload-evoked pathological cardiac remodeling via mitogen activated protein kinase-activated protein kinase-5 (MK5). However, myocardial ERK3 does not activate MK5, thus the role of myocardial ERK3 remains unclear. Through in vivo and in vitro experiments, we revealed that myocardial ERK3 expression increases under pressure overload and the protein accumulates significantly in the nucleus. Using cardiomyocyte-specific Erk3-deficient mice, neonatal rat cardiomyocytes and adult mouse cardiomyocytes, we found that cardiomyocyte-specific Erk3 deficiency ameliorated pressure overload-induced pathological cardiac remodeling in vivo. Co-immunoprecipitation, mass spectrometry, and single nucleus RNA sequencing were used to analyse for the nuclear translocation and downstream signaling mechanisms of ERK3. Specifically, pressure overload enhances the binding of Aly/REF export factor (ALY) to ERK3, resulting in the truncation of the ERK3 C-terminal and its subsequent nuclear translocation to activate the thioredoxin-interacting protein (TXNIP)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway through the expression of the splicing factor proline and glutamine rich (SFPQ). To screen for targeted drugs, we conducted a virtual screening and identified estrone sulfate as an inhibitor of ALY to counteract hypertrophic effects. Collectively, our findings indicate that estrone sulfate functions as a novel inhibitor of the ALY-ERK3 signaling pathway, potentially serving as a promising therapeutic candidate for the management of pathological cardiac remodeling.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148992971","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}