Hamadan University of Medical Sciences Avicenna Journal of Medical Biochemistry 2345-4113 13 2 2025 12 31 Effect of Metformin on the Expression and Action of FOXO1, RAGE, Nrf2, and SIRT1 in Diabetes-Associated Disorders: A Review Article 127 134 10.34172/ajmb.2634 EN Seyed Yousef Kariminejad https://orcid.org/0009-0003-3703-2639 Hashem Hosseinipoor Mozhdeh Heidari Mohammad Taghi Goodarzi https://orcid.org/0000-0002-5546-5812 Mohammad Hossein Karimi https://orcid.org/0000-0002-2435-6277 REVIEW 10.34172/ajmb.2634 2025 09 27 2025 11 13 Type 2 diabetes (T2D) is one of the most prevalent, multisystemic, and chronic metabolic disorders that is characterized by the presence of oxidative stress (OS) and mitochondrial dysfunction, leading to different pathologic conditions. Various genes and their coding proteins, such as nuclear factor erythroid 2-related factor 2 (NrF2), receptor for advanced glycation end products (RAGE), silent information regulator 1 (SIRT1), and forkhead box transcription factor O1 (FOXO1), can considerably alleviate diabetes-induced OS production, mitochondrial dysfunction, and insulin resistance. In this regard, metformin is considered one of the safest and first-line oral therapies for T2D. Accordingly, this review has focused on the effect of metformin on the expression levels of NrF2, RAGE, SIRT1, and FOXO1 in diabetes-associated disorders. It is noteworthy that metformin can play an important role in the etiopathology of T2D through a variety of molecular pathways involving genes and the expression of their coding proteins, such as NrF2, RAGE, SIRT1, and FOXO1.