DISRUPTED ARGININE–NITRIC OXIDE SIGNALING IN SICKLE CELL DISEASE: MOLECULAR MECHANISMS, PATHOPHYSIOLOGICAL CONSEQUENCES AND EMERGING THERAPEUTIC TARGETS

_1757918524 20250915064204000 Editor editor.jddt@gmail.com Universal Journal of Pharmaceutical Research Universal Journal of Pharmaceutical Research Univ J Pharm Res 2456-8058 2831-5235 09 15 2025 DISRUPTED ARGININE–NITRIC OXIDE SIGNALING IN SICKLE CELL DISEASE: MOLECULAR MECHANISMS, PATHOPHYSIOLOGICAL CONSEQUENCES AND EMERGING THERAPEUTIC TARGETS Emmanuel Ifeanyi Obeagu Christian C. Ezeala Sickle cell disease (SCD) is marked by ongoing hemolysis and blood vessel dysfunction, with the arginine–nitric oxide (NO) pathway being crucial to its pathophysiology. This review examines the molecular mechanisms that contribute to the disruption of the arginine–NO axis in SCD, emphasizing how hemolysis-mediated arginase release reduces L-arginine, the precursor for NO production, while cell-free hemoglobin captures bioactive NO. Moreover, increased concentrations of natural NOS inhibitors like asymmetric dimethylarginine (ADMA) and oxidative stress play a role in the uncoupling of nitric oxide synthase (NOS), which further diminishes NO bioavailability. Impaired citrulline–arginine recycling worsens substrate shortage, together resulting in endothelial dysfunction, vasoconstriction, and inflammation. Therapeutic strategies aimed at this pathway, such as arginine and citrulline supplementation, arginase inhibition, antioxidants, and NO donors, are examined, highlighting their ability to restore vascular balance. Peer Review History: Received 5 June 2025; Reviewed 11 July 2025; Accepted 20 August; Available online 15 September 2025 Academic Editor: Dr. Gehan Fawzy Abdel Raoof Kandeel, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt, gehankandeel9@yahoo.com Reviewers: Dr. Barkat Ali Khan, Kampala International University , Uganda, barki.gold@gmail.com Dr. Bilge Ahsen KARA, Ankara Gazi Mustafa Kemal Hospital, Turkey, ahsndkyc@gmail.com 09 15 2025 http://creativecommons.org/licenses/by-nc/4.0 10.22270/ujpr.v10i4.1394 https://ujpronline.com/index.php/journal/article/view/1394 https://ujpronline.com/index.php/journal/article/download/1394/1945 https://ujpronline.com/index.php/journal/article/download/1394/1945 https://ujpronline.com/index.php/journal/article/download/1394/1959 https://ujpronline.com/index.php/journal/article/download/1394/1975