Cardiac glycosides toxicity: Mechanisms and mitigation strategies in recent studies

Cardiac glycosides, while renowned for their cardiotonic effects, present a significant challenge in drug development due to their narrow therapeutic window. Although their antitumor potential, exemplified by derivatives such as RX108 entering clinical trials, has renewed research interest, inherent cardiotoxicity remains a major safety concern. This review focuses on recent advances in understanding and mitigating cardiac glycoside toxicity. A central focus is placed on comprehensively summarizing the intricate molecular mechanisms underlying their cardiotoxicity, which extend beyond the canonical Na⁺/K⁺-ATPase inhibition. In addition, we examine their multi-organ toxicity profiles and corresponding clinical management strategies, with particular emphasis on digoxin-specific Fab antibodies. Another pivotal aspect of this review is a critical analysis of contemporary, rational structural modification strategies designed to decouple cardiotoxicity from therapeutic efficacy. By synthesizing these insights, this work aims to provide a foundational framework for overcoming the toxicity hurdles and advancing the repurposing of cardiac glycosides in precision oncology and other therapeutic areas.