NLRP3 inflammasome inhibition by dehydroisohispanolone confers cardioprotection against doxorubicin-induced cardiotoxicity
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Fernández Vega, Eva [1] ; Heras, Beatriz de las [1] ; Hortelano, Sonsoles [2] ; Cuadrado null, Irene [1]
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[1] Universidad Complutense de Madrid
Universidad Complutense de Madrid
Madrid, España
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[2] Instituto de Salud Carlos III
Instituto de Salud Carlos III
Madrid, España
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- Localización: Dianas: revista de dianas terapéuticas, ISSN-e 1886-8746, Vol. 14, Nº. 1, 2025 (Ejemplar dedicado a: Actas del X Congreso de Señalización Celular, SECUAH 2025)
- Idioma: inglés
- Texto completo no disponible (Saber más ...)
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Resumen
Cardiovascular diseases and cancer are among the leading global health challenges. Doxorubicin (DOX), a widely prescribed chemotherapeutic agent, has effective anticancer effects but is associated with severe cardiotoxicity. Growing evidence highlights the key role of inflammasomes, particularly NLRP3, in DOXinduced damage. NLRP3 activation leads to the release of proinflammatory cytokines IL-1β and IL-18, and triggers pyroptotic cell death. Thus, targeting the inflammatory response driven by the NLRP3 inflammasome may offer a promising strategy to mitigate this cardiotoxicity. Diterpenes are promising cardioprotective agents. Among them, dehydroisohispanolone (DIH), derived from the labdane diterpene hispanolone, has exhibited both anti-inflammatory and cardioprotective properties against myocardial infarction and has recently been identified as an NLRP3 inhibitor. This study evaluates the cardioprotective effects of DIH against DOX-induced toxicity. AC16 cardiomyocytes and THP-1 macrophages were used to assess the effects of DIH. Our results revealed that DIH significantly reduced the release of pro-inflammatory interleukins IL-1β and IL-18 and decreased pyroptotic cell death in both cell types. Furthermore, DIH impaired caspase-1 activation in cardiomyocytes and reduced the expression of gasdermin-N and pro- and cleaved forms of caspase-1 and IL-1β. Importantly, DIH also exerted immunoprotective effects in THP-1 macrophages, suggesting its potential to preserve immune cell function during DOX treatment. Overall, these findings highlight DIH as a promising cardioprotective and anti-inflammatory agent capable of mitigating DOX-induced cardiotoxicity, underscoring its therapeutic potential in cancer treatment.
