Biology Direct最新文献

{"title":"Dualistic role of ZEB1 and ZEB2 in tumor progression.","authors":"Sergey E Parfenyev, Alexandra A Daks, Oleg Y Shuvalov, Olga A Fedorova, Nikolay B Pestov, Tatyana V Korneenko, Nickolai A Barlev","doi":"10.1186/s13062-025-00604-3","DOIUrl":"10.1186/s13062-025-00604-3","url":null,"abstract":"<p><p>It is generally accepted that ZEB1 and ZEB2 act as master regulators of the epithelial-mesenchymal transition, which arguably is the key mechanism of metastasis. Accordingly, they are deemed as negative predictors of the survival of cancer patients by promoting the emergence of secondary foci of the disease. Paradoxically, in some types of cancer types the opposite effect is observed, i.e. ZEB1 and ZEB2 are associated with better prognosis for cancer patients. In this review, we discuss the hypothesis that the tumorigenic effects of ZEB1/ZEB2 can be different in various tissues depending on the initial status of these proteins in the corresponding healthy tissues. Emerging evidence suggests that ZEB1 and ZEB2 are constitutively expressed in several healthy tissues, performing vital functions. Consequently, reducing the expression of ZEB1 and ZEB2 could negatively affect these tissues causing various diseases, including cancer. Finally, the dualistic role of ZEB1 and ZEB2 as immune modulators and their effect on tumor microenvironment is also discussed.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"32"},"PeriodicalIF":5.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma N-Glycoproteomics in monozygotic twin pairs discordant for body mass index reveals an obesity signature related to inflammation and iron metabolism.","authors":"Maheswary Muniandy, Sakari Joenväärä, Birgitta W van der Kolk, Tiialotta Tohmola, Hanna Haltia, Sina Saari, Antti Hakkarainen, Jesper Lundbom, Juho Kuula, Per-Henrik Groop, Jaakko Kaprio, Sini Heinonen, Risto Renkonen, Kirsi H Pietiläinen","doi":"10.1186/s13062-025-00609-y","DOIUrl":"10.1186/s13062-025-00609-y","url":null,"abstract":"<p><strong>Background: </strong>N-glycosylation is a complex, post-translational modification which influences protein function and is sensitive to physiological changes. Obesity is associated with alterations in protein function; however, little is known about the glycoproteome in obesity beyond observations of association with types and structures of selected glycopeptides. Most often, due to technical challenges, glycan composition and structure information are missing. Here, we combined label-free data-independent proteomics and targeted quantitative glycoproteomics to study N-glycosylation of plasma proteins in obesity. Using a monozygotic twin study design, we controlled for genetic variation and focused only on the acquired effects of obesity.</p><p><strong>Methods: </strong>Using plasma samples of 48 monozygotic twin pairs discordant for BMI (intrapair difference > 2.5 kg/m²), we identified using mass spectrometry, differential protein and glycopeptide levels between heavier and leaner co-twins. We used a within-twin paired analysis model and considered p < 0.05 as significant.</p><p><strong>Results: </strong>We identified 48 protein and 33 N-glycosylation expression differences (p < 0.05) between co-twins. These differences occurred either both in the protein expression and glycoprotein (sometimes in opposing directions) or independently from each other. Haptoglobin protein was upregulated (Fold Change = 1.10, p = 0.001) in heavier co-twins along with seven upregulated glycan compositions at N-glycosylation site Asn241. The complement protein C3 was upregulated (Fold Change = 1.08, p = 0.014) along with one upregulated glycopeptide at Asn85. Additionally, many glycopeptides were upregulated despite non-significant differences in protein-backbone plasma levels.</p><p><strong>Conclusion: </strong>Differential protein expression related to cholesterol biosynthesis and acute phase signalling as well as N-glycosylation of proteins related to iron metabolism and inflammation can be linked to acquired obesity.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"31"},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage-derived SPP1 exacerbate myocardial injury by interacting with fibroblasts in viral myocarditis.","authors":"Xiuyun Duan, Li Zhang, Keyu Liu, Kaiyin Guo, Yingnan You, Hailin Jia, Shan Zhou, Bo Han","doi":"10.1186/s13062-025-00621-2","DOIUrl":"10.1186/s13062-025-00621-2","url":null,"abstract":"<p><strong>Background: </strong>Viral myocarditis (VMC) is an inflammatory myocardial condition triggered by viral infections which involves pathogenic-related damage and immune-mediated damage. However, the precise immunopathogenic mechanisms underlying VMC remain elusive.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing on mouse hearts during the acute phase of CVB3-induced VMC. After manually annotating cell types, functional analyses of macrophage were performed by cell ratio changes, customized gene set module scoring and CellPhoneDB. Utilizing indirect co-culture experiments in vitro, the effects of macrophage-derived SPP1 on cardiac fibroblasts were investigated. Depletion of macrophages and inhibition of SPP1 expression in mice were carried out to study the effects of macrophage-derived SPP1 on cardiac function, inflammation levels, and myocardial injury in mice with VMC.</p><p><strong>Results: </strong>Our data revealed that macrophages are the major immune cells which infiltrate the heart during the acute phase of VMC, particularly a macrophage subpopulation which highly expresses Spp1 (Spp1⁺ macrophages) and exhibited characteristics of peripheral blood monocytes. Spp1⁺ macrophages communicate extensively with fibroblasts during VMC, and that SPP1 promotes fibroblast conversion to an inflammatory phenotype with high Ccl2/Ccl7 expression. This in turn increases monocyte chemotaxis to the heart. Besides, a partial depletion of macrophages in the early stages of VMC attenuated myocardial inflammation and myocardial injury in mice. Inhibition of SPP1 reduced cardiac macrophage infiltration, attenuated myocardial inflammation, and improved cardiac function in VMC mice.</p><p><strong>Conclusion: </strong>Our findings suggested that Spp1⁺ macrophages could self-recruit, and macrophage-derived SPP1 exacerbated myocardial immune injury by promoting high Ccl2/Ccl7 expression in fibroblasts. Our study advances understandings of VMC pathogenesis, and provides novel insight into potential immunotherapies for VMC.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"30"},"PeriodicalIF":5.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of estrogen in the sex difference for the risk factors of heart failure with preserved ejection fraction.","authors":"Jun Du, Jiaqi Liu, Xiaoya Wang, Xiaowu Wang, Yu Ma, Sipan Zhang, Zilin Li, Jipeng Ma, Jincheng Liu","doi":"10.1186/s13062-025-00618-x","DOIUrl":"10.1186/s13062-025-00618-x","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) is a major subtype of heart failure, primarily characterized by a normal or mildly reduced left ventricular ejection fraction along with left ventricular diastolic dysfunction. Recent studies have shown that the prevalence of HFpEF is higher in women than that in men, particularly in postmenopausal women. Concurrently, it has been observed that the incidence of risk factors contributing to HFpEF (such as obesity, hypertension, diabetes, and atrial fibrillation) also notably increases post-menopause, affecting the incidence of HFpEF. This review aimed to examine the relationship between estrogen and risk factors associated with HFpEF, clarifying the underlying mechanisms through which estrogen affects these risk factors from epidemiological and pathophysiological perspectives. This review also provides a comprehensive understanding of the association between estrogen and the risk factors for HFpEF, thus helping explore potential targets for HFpEF treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"28"},"PeriodicalIF":5.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential growth and flowering capacity of tulip bulbs and the potential involvement of PHOSPHATIDYLETHANOLAMINE-BINDING PROTEINS (PEBPs).","authors":"Francesca Bellinazzo, Irene Manders, Bas Heidemann, Manuel Aguirre Bolanos, Evelien Stouten, Jacqueline Busscher, Dolores Abarca, Froukje van der Wal, Marcelo Carnier Dornelas, Gerco C Angenent, Marcel Proveniers, Harm Nijveen, Richard G H Immink","doi":"10.1186/s13062-025-00625-y","DOIUrl":"10.1186/s13062-025-00625-y","url":null,"abstract":"<p><strong>Background: </strong>Tulipa gesneriana reproduces vegetatively by the development of bulb clusters from axillary meristems in the scales of a mother bulb. While part of the daughter bulbs in a cluster develop into large, flowering bulbs, others stay small and vegetative under the same environmental conditions. This study aims to investigate how these different developmental fates are orchestrated.</p><p><strong>Results: </strong>RNA-seq analysis revealed that the overall transcriptomic landscape of the two types of daughter bulbs does not differ substantially, but follows a similar trajectory over time. Nonetheless, the expression levels of genes related to proliferation already differ at early development stages. Surprisingly, at a later stage, transcriptomic changes related to flower induction are detectable in flowering as well as non-flowering bulbs, with some quantitative differences. However, genes linked with floral organ development are differentially expressed, as well as negative regulators of flowering and more basal metabolic processes. In search for the molecular determinants of daughter bulb size and developmental fate, we investigated members of the PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN (PEBP) gene family as candidates. Tulip FLOWERING LOCUS T1 (TgFT1), TgFT2, and TgFT3 are expressed in leaves and leaf-like organs of the mother plant, and their encoded proteins interact with the TCP transcription factor TEOSINTE BRANCHED1 (TgTB1). Therefore, we suggest that these three genes act as 'bulbigens', meaning regulators of axillary meristem outgrowth and hence, daughter bulb size. Furthermore, we found that TgFT2 and TgFT4 could constitute the main florigens in tulips, because of their expression pattern and the binding of their encoding proteins to the bZIP transcription factor FD (TgFD). Moreover, Arabidopsis lines ectopically expressing TgFT2 or TgFT4 flower significantly earlier than the wild type.</p><p><strong>Conclusions: </strong>Differences in the developmental fate of tulip daughter bulbs are established early during development and are linked with differences in cell division and metabolism. The activity of members of the PEBP family, known for their role in flowering and storage organ formation in geophytes, appeared to be associated with the transcriptional switches observed during daughter bulb development. This points towards a functional role of these proteins in governing developmental trajectories underlying the mode of reproduction.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"29"},"PeriodicalIF":5.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification.","authors":"Enshuang Guo, Lei Li, Jiankun Yang, Yongjian Zhou, Lu Bai, Weiwei Zhu, Qiuyue Hu, Huifen Wang, Hongqiang Liu","doi":"10.1186/s13062-025-00620-3","DOIUrl":"10.1186/s13062-025-00620-3","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma is a fatal malignancy that lacking specific therapies. Homeobox B4 (HOXB4) was negatively correlated with poor prognosis in cancers, but its role in hepatocellular carcinoma has not been elucidated.</p><p><strong>Results: </strong>We confirmed that HOXB4 was downregulated in hepatocellular carcinoma tissues and lower HOXB4 expression associated with poor prognosis. Gain- and loss-of function experiments were performed to understand the functional consequences. We revealed that HOXB4 overexpression inhibited proliferation and metastasis of hepatocellular carcinoma cells, accompanied with the decrease in epithelial-mesenchymal transition and increase in cell apoptosis. Database analysis showed that HOXB4 was positively correlated with the immune infiltration. PD-L1 expression was decreased in HOXB4 overexpressed hepatocellular carcinoma cells. HOXB4 overexpression was confirmed to inhibit the progression of hepatocellular carcinoma and promote T cell infiltration in vivo. N6-methyladenosine (m6A) modification was implicated in the tumorigenesis. RNA-seq analysis showed that HOXB4 overexpression modulated METTL7B expression. With the performance of dual-luciferase reporter, ChIP, and DNA pulldown assays, we revealed that HOXB4 binding to METTL7B promoter and inhibited its mRNA expression. The increased aggressiveness of hepatocellular carcinoma cells and the enhanced immune escape, triggered by HOXB4 knockdown, were inhibited via METTL7B downregulation. Methylated RNA immunoprecipitation assay displayed that METTL7B controlled the mRNA decay of TKT in m6A methylation. METTL7B overexpression increase the expression of TKT, ultimately promoting hepatocellular carcinoma progression and immune evasion.</p><p><strong>Conclusions: </strong>HOXB4 mediated the malignant phenotypes and modulated the immune evasion via METTL7B/TKT axis. The HOXB4/METTL7B cascade and its downstream changes might be novel targets for blocking hepatocellular carcinoma progression.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"26"},"PeriodicalIF":5.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma.","authors":"Xu Zhang, Fayu Liu, Qigen Fang, Changfu Sun, Jie Fan","doi":"10.1186/s13062-025-00622-1","DOIUrl":"10.1186/s13062-025-00622-1","url":null,"abstract":"<p><strong>Background: </strong>Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related mortality worldwide due to its high aggressive potential and drug resistance. Previous studies have revealed an important function of HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (HERC5) in cancer. Six GEO gene microarrays identified HERC5 as a significant upregulated gene in OSCC tissues or cells (log2 Fold change > 1 and adj.p < 0.05). This study aimed to explore the role and underlying mechanisms of HERC5 in OSCC development.</p><p><strong>Results: </strong>High HERC5 expression in OSCC tissues was confirmed by our hospital validation cohort and positively correlated with primary tumor stages. Subsequent functional studies demonstrated that knockdown of HERC5 inhibited the migratory and invasive capabilities with decrease of Vimentin and increase of E-cadherin in OSCC cells. In cisplatin treatment, cell survival rates were significantly reduced in HERC5-silencing OSCC cells, accompanied by the increase in cytotoxicity, DNA damage and apoptosis. OSCC cell-derived tumor xenograft displayed that HERC5 depletion inhibited pulmonary metastasis as well as restored the cisplatin-induced tumor burden. In line with this, overexpression of HERC5 yielded the opposite alterations both in vivo and in vitro. Mechanistically, UDP-glucose 6-dehydrogenase (UGDH) was identified as a HERC5-binding protein. Cysteine residue at position 994 in the HECT domain of HERC5 catalyzed the conjugation of ubiquitin-like protein Interferon-induced 15 kDa protein (ISG15) to UGDH (ISGylation of UGDH) and facilitated its phosphorylation, therefore enhancing SNAI1 mRNA stability. SNAI1 depletion inhibited HERC5 overexpression-triggered invasion and cisplatin resistance of OSCC cells.</p><p><strong>Conclusions: </strong>Our study indicates that HERC5 may be a promising therapeutic target for OSCC.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"27"},"PeriodicalIF":5.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moving biology direct towards a new dimension.","authors":"Gerry Melino","doi":"10.1186/s13062-025-00619-w","DOIUrl":"10.1186/s13062-025-00619-w","url":null,"abstract":"","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"25"},"PeriodicalIF":5.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleolin in the cell membrane promotes Ang II-mediated VSMC phenotypic switching by regulating the AT1R internalization function : Nucleolin promotes Ang II-mediated VSMC phenotypic switching.","authors":"Li Fang, Zhijie Shen, Yinzhuang Zhang, Zhuoni Mao, Dan Huang, Chenyu Lou","doi":"10.1186/s13062-025-00615-0","DOIUrl":"10.1186/s13062-025-00615-0","url":null,"abstract":"<p><strong>Background: </strong>Nucleolin (NCL) plays an important regulatory role in angiotensin II (Ang II)-induced phenotypic switching of vascular smooth muscle cells (VSMCs). The aim of this study was to discuss its potential regulatory mechanisms.</p><p><strong>Results: </strong>We investigated if the pathways involving Ang II type 1 receptor (AT1R) and PKC/MAPK are responsible for Ang II's effects on VSMC phenotypic switching. Ang II upregulated NCL expression and activated the PKC/MAPK signaling pathway to induce VSMC phenotypic switching. In addition, Ang II promoted the translocation of NCL from the nucleus to the cell membrane. NCL was shown to bind to AT1R, whereas the binding of NCL to AT1R was greatly attenuated after the deletion of the GAR region. In addition, when peptide-N-glycosidase F (PNGase F) was applied, the N-glycosylation of NCL protein and the phenotypic switching of VSMC were inhibited. Ang II-induced AT1R internalization, whereas overexpression of NCL delayed Ang II-induced AT1R internalization by inhibiting AT1R phosphorylation and recruited Rab4 and Rab11 to promote recycling, and knockdown of NCL showed the opposite effect and reversal of AT1R binding by the use of rasarfin reversed the effects of sh-NCL. In in vivo experiments, knockdown of NCL expression inhibited Ang II-induced blood pressure rise and vasculopathy.</p><p><strong>Conclusions: </strong>Our study demonstrates that NCL promotes Ang II-mediated phenotypic switching of VSMCs by regulating AT1R internalization function.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"24"},"PeriodicalIF":5.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sigma-1 receptor activation attenuates DOX-induced cardiotoxicity by alleviating endoplasmic reticulum stress and mitochondrial calcium overload via PERK and IP3R-VDAC1-MCU signaling pathways.","authors":"Zixuan Li, Qian Ran, Chuan Qu, Shan Hu, Shengyu Cui, You Zhou, Bo Shen, Bo Yang","doi":"10.1186/s13062-025-00617-y","DOIUrl":"10.1186/s13062-025-00617-y","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin (DOX) is an anthracycline with potent antitumor properties and rare yet serious cardiotoxic side effects that limit its clinical application. The sigma-1 receptor is a stress-triggered chaperone often dysregulated in diseases and has known cardioprotective effects. Although its anti-oxidative stress and anti-apoptotic effects have been demonstrated, its effectiveness in DOX-induced cardiotoxicity has never been explored. This study investigated the potential role of the activated sigma-1 receptor in a DOX-induced murine cardiotoxicity model to elucidate the receptor's mechanism of action.</p><p><strong>Methods: </strong>We established the model in C57BL/6 mice by daily intraperitoneal injections of fluvoxamine (Flv) for 4 consecutive weeks to activate the receptor and by weekly intraperitoneal injections of DOX at 5 mg/kg for 3 weeks. We performed in vitro experiments using cardiomyocytes of neonatal Sprague-Dawley rats to verify the protective effect of the sigma-1 receptor.</p><p><strong>Results: </strong>We found that sigma-1 expression in the heart decreased in the DOX-treated mice, and activating the receptor with Flv improved cardiac function. Moreover, Flv pretreatment inhibited cardiomyocyte apoptosis and endoplasmic reticulum stress and increased the expression of the Bcl2 apoptosis regulator (Bcl2), effectively alleviating the pathophysiological manifestations in mice. In addition, activating the receptor exerted cardioprotective effects by modulating endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase (PERK) signaling pathway. It also reduced mitochondrial and endoplasmic reticulum contact and alleviated mitochondrial calcium overload through the IP3R-VDAC1-MCU signaling pathway.</p><p><strong>Conclusion: </strong>In conclusion, our study emphasizes the therapeutic potential of activating sigma-1 receptors against DOX-induced cardiotoxicity, suggesting sigma-1 receptors as potential therapeutic targets for this disease.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"23"},"PeriodicalIF":5.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}