{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:49:31Z","timestamp":1790221771656,"version":"4.1.0"},"reference-count":318,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Council of Mexico (CONAHCYT)","award":["CF-2019-7357"],"award-info":[{"award-number":["CF-2019-7357"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cardiac glycosides (CGs), a class of plant- and animal-derived compounds historically used to treat heart failure, have garnered renewed interest for their diverse pharmacological properties beyond Na+\/K+-ATPase (NKA) inhibition. Recent studies reveal that CGs modulate key signaling pathways\u2014such as NF-\u03baB, PI3K\/Akt, JAK\/STAT, and MAPK\u2014affecting processes central to cancer, viral infections, immune regulation, and neurodegeneration. In cancer, CGs induce multiple forms of regulated cell death, including apoptosis, ferroptosis, pyroptosis, and immunogenic cell death, while also inhibiting angiogenesis, epithelial\u2013mesenchymal transition, and cell cycle progression. They demonstrate broad-spectrum antiviral activity by disrupting viral entry, replication, and mRNA processing in viruses such as HSV, HIV, influenza, and SARS-CoV-2. Immunologically, CGs regulate Th17 differentiation via ROR\u03b3 signaling, although both inhibitory and agonistic effects have been reported. In the nervous system, CGs modulate neuroinflammation, support synaptic plasticity, and improve cognitive function in models of Alzheimer\u2019s disease, epilepsy, and multiple sclerosis. Despite their therapeutic potential, clinical translation is hindered by narrow therapeutic indices and systemic toxicity. Advances in drug design and nanocarrier-based delivery are critical to unlocking CGs\u2019 full potential as multi-target agents for complex diseases. This review synthesizes the current knowledge on the emerging roles of CGs and highlights strategies for their safe and effective repurposing.<\/jats:p>","DOI":"10.3390\/biom15060885","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T11:53:14Z","timestamp":1750161194000},"page":"885","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Cardiac Glycosides: From Natural Defense Molecules to Emerging Therapeutic Agents"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-5210","authenticated-orcid":false,"given":"Arturo","family":"Ponce","sequence":"first","affiliation":[{"name":"Department of Physiology, Biophysics and Neurosciences, CINVESTAV-Instituto Politecnico Nacional, Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-0694","authenticated-orcid":false,"given":"Catalina","family":"Flores-Maldonado","sequence":"additional","affiliation":[{"name":"Department of Physiology, Biophysics and Neurosciences, CINVESTAV-Instituto Politecnico Nacional, Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7311-1615","authenticated-orcid":false,"given":"Ruben G.","family":"Contreras","sequence":"additional","affiliation":[{"name":"Department of Physiology, Biophysics and Neurosciences, CINVESTAV-Instituto Politecnico Nacional, Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"540","DOI":"10.5694\/j.1326-5377.1986.tb112283.x","article-title":"Naturally Occurring Cardiac Glycosides","volume":"144","author":"Radford","year":"1986","journal-title":"Med. 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