ArticleBiology direct2025
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.
Article in Biology direct, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Calcium overload-induced apoptosis in cancer cells: ER-mitochondria crosstalk and therapeutic implications.Pharmaceutical science advances · 2026Review
- Calcium overload induces reactive oxygen species to enhance glioblastoma radiosensitivity.Medical gas research · 2026Article
- Cuproptosis: Biomarkers, Mechanisms and Treatments in Diseases.Molecules (Basel, Switzerland) · 2026Review
- Crosstalk Between the Endoplasmic Reticulum and Mitochondria in Skeletal Muscle: Implications for Meat Quality.Animals : an open access journal from MDPI · 2025Review
- Review
- Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.Neurochemical research · 2025Review
- Intracellular Calcium Dysregulation: The Hidden Culprit in the Diabetes-Gout Nexus.Biomedicines · 2025Review
- Dynamic expression of the myocardial sigma-1 receptor after doxorubicin cardiomyopathy using radioiodine-labeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5 V) imaging.Annals of nuclear medicine · 2025Article
- Dual Roles of Autophagy in Radiation-Induced Brain Injury: Mechanistic Insights and Therapeutic Implications.CNS neuroscience & therapeutics · 2025Review
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDoxorubicin (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.
methodsWe 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.
resultsWe 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.
conclusionIn 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.
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