The PI3K/AKT/eNOS Signaling Axis: Molecular Mechanisms and Therapeutic Implications in Cardiovascular and Metabolic Disorders
Anuj Kumar Sharma, Robin Singh, Raj Kumar Tiwari, Kamal Kant Ravi, Amit Singh, Bhupesh Kumar, Suparna Sharma, Garima GargIntroduction:
The PI3K/AKT-eNOS signalling axis - including phosphoinositide 3- kinase (PI3K)/protein kinase B (AKT)-endothelial nitric oxide synthase (eNOS) - is a crucial molecular pathway that governs vascular tone, blood circulation, glucose metabolism, and cellular survival, thereby upholding cardiovascular and metabolic homeostasis. The dysregulation of this pathway is strongly associated with the development of major disorders, including hypertension, atherosclerosis, diabetes, obesity, and non-alcoholic fatty liver disease.
Methods:
A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, Web of Science, Embase, and Google Scholar to identify studies published from January 2005 to March 2026. The search used keyword combinations including PI3K/AKT, eNOS, nitric oxide, endothelial dysfunction, cardiovascular disease, and related terms.
Result:
Therapeutic strategies to manipulate this axis are thus a promising avenue for disease management protocols. Pharmacological modulation of PI3K isoforms, AKT activity, and eNOS function can restore endothelial integrity and improve metabolic balance.
Discussion:
Additionally, combination therapies targeting multiple components of this pathway or interconnected signaling systems may be more effective in treating the condition and may overcome resistance. Emerging biotechnological approaches, including gene therapy, RNA interference, nanotechnology-based drug delivery, and genome editing with zinc finger nucleases (ZFNs) targeting human cell-cycle genes, offer novel, tissue-specific opportunities for controlling this signaling cascade.
Conclusion:
The PI3K/AKT-eNOS axis is a key regulator in cardiovascular and metabolic diseases. Further exploration with advanced biotechnological tools is essential for developing more precise, effective, and safe next-generation therapies.