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Ambrisentan attenuates cisplatin-related mitochondrial dysfunction in the heart via regulation of p53 and NF-κB signaling

Year: 2026

Type: article

Abstract: ) antagonist, confers beneficial effects in cardiovascular diseases, but its role in mitigating chemotherapy-induced cardiotoxicity remains unexplored. This study investigates the protective effects of ambrisentan against cisplatin-induced cardiotoxicity in H9c2 cardiomyoblasts, focusing on its regulatory role via the p53 and NF-κB signaling pathways. Ambrisentan reduced cisplatin-induced apoptosis by downregulating caspase-3/7 activity and BAX expression while upregulating Bcl-2. Cisplatin-induced inflammation was also attenuated by ambrisentan through the reduction of TNFα and IL6 levels. Furthermore, ambrisentan protected cells against cisplatin-induced mitochondrial damage by lowering ROS levels, promoting mitochondrial fusion (OPA1, MFN1), inhibiting fission (DNM1, FIS1), and enhancing mitochondrial biogenesis (ATP5A, NRF1, PGC1α). Structured illumination microscopy revealed that ambrisentan preserved tubular mitochondrial morphology and reversed cisplatin-induced fragmentation. In addition, ambrisentan restored mitochondrial respiration and glycolysis, evidenced by improved oxygen consumption rate and extracellular acidification rate, along with increased pro-survival molecules (p-Akt and p-Erk1/2), under cisplatin-mediated stress. Mechanistically, pharmacological inhibition of p53 and NF-κB enhanced the protective effects of ambrisentan, whereas their activation exacerbated cisplatin-induced cardiac injury. Therefore, ambrisentan may serve as a potential agent for suppressing apoptosis, inflammation, and mitochondrial impairments, offering protection against cisplatin-associated cardiotoxicity through modulation of the p53 and NF-κB pathways.

Source: Scientific Reports

DOI: 10.1038/s41598-026-44822-9

Authors: Hnin Ei Ei Khine, Supachoke Mangmool, Warisara Parichatikanond

Institutions: Mahidol University, Chiang Mai 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: $2,690