Cardiac glycosides: Looking beyond heart failure and atrial fibrillation.

Cardiac glycosides, historically used for managing heart failure and atrial fibrillation, have demonstrated significant pharmacological versatility extending into oncology, virology, and immunotherapy. By targeting Na/K-ATPase, these compounds regulate ionic homeostasis and initiate signalosome formation, influencing key pathways such as MAPK/ERK and PI3K/Akt. Beyond their cardiovascular effects, cardiac glycosides exhibit potent immunomodulatory and senolytic properties, particularly in cancer therapy. They induce immunogenic cell death by releasing damage-associated molecular patterns, which enhance tumor antigen presentation and activate cytotoxic T lymphocytes. In addition, their ability to selectively eliminate senescent tumor cells through Na/K-ATPase inhibition reduces inflammation and improves therapeutic outcomes in synergistic cancer treatments. Furthermore, their antiviral activities have been explored against SARS-CoV-2 and Ebola virus infections, with mechanisms involving the disruption of viral entry, replication, and protein synthesis. Despite their promise, concerns about cardiotoxicity and a narrow therapeutic window persist, necessitating precise dosing and novel derivatives with improved safety profiles. This review consolidates current insights into the mechanisms, therapeutic applications, and limitations of cardiac glycosides, highlighting their potential as a cornerstone for future drug development in oncology and infectious diseases. Advancing pharmacogenomic approaches and clinical trials will further define their role in precision medicine.