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MiR ‐145‐5p Attenuates Doxorubicin‐Induced Heart Injury Through Targeting Cardiomyocyte Pyroptosis

Year: 2025

Type: article

Abstract: Doxorubicin (DOX), a potent anthracycline chemotherapeutic, exhibits dose-dependent cardiotoxicity that limits its clinical utility. Although miR-145-5p demonstrates cardioprotective properties in cardiovascular diseases, its role in DOX-induced cardiomyopathy remains undefined. This study investigated the therapeutic potential of miR-145-5p against DOX-induced cardiotoxicity and its underlying mechanism. Wistar rats received cumulative DOX dosing (15 mg/kg total) to establish cardiotoxicity, with miR-145-5p overexpression achieved via adeno-associated virus serotype 9 (AAV9) delivery. Cardiac function was assessed by echocardiography and serum biomarkers, including creatine kinase-MB isoenzyme (CK-MB), cardiac troponin T (c-TnT), C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Histopathology (Hematoxylin & Eosin/Masson's Trichrome staining), apoptosis (TUNEL), oxidative stress (dihydroethidium staining/malondialdehyde/glutathione), and NLRP3 inflammasome activation (ELISA/Western blot/immunohistochemistry) were evaluated. Clinical relevance was determined by quantifying serum miR-145-5p and SOX9 mRNA in healthy controls and breast cancer patients before and after DOX treatment. DOX significantly downregulated miR-145-5p and upregulated SOX9 in rat myocardium and H9C2 cells. DOX-treated patients displayed reduced serum miR-145-5p and increased SOX9 mRNA compared with pre-chemotherapy baselines. AAV9-miR-145-5p attenuated DOX-induced systolic dysfunction, reduced serum biomarkers, ameliorated histopathological injury and fibrosis, suppressed apoptosis and oxidative stress, and inhibited NLRP3 inflammasome activation (decreased NLRP3, ASC, caspase-1, IL-1β, and IL-18). miR-145-5p directly targeted the SOX9 3'UTR, and SOX9 overexpression reversed miR-145-5p-mediated reductions in CK release, ROS production, apoptosis, and NLRP3 expression in H9C2 cells. These findings demonstrate that miR-145-5p protects against DOX cardiotoxicity by targeting SOX9 to inhibit NLRP3 inflammasome-mediated pyroptosis, offering a potential therapeutic strategy.

Source: The Kaohsiung Journal of Medical Sciences

DOI: 10.1002/kjm2.70126

Authors: Xing‐Tao Chen, Yong‐Hong Yu, Yan‐Hua Du, Lin Xu, Xiang‐Ping Meng

Institutions: Wuhan Puai Hospital, Renmin Hospital of Wuhan University

Language: English

Topic: Chemotherapy-induced cardiotoxicity and mitigation

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,200