The direct targets of metformin in diabetes and beyond

HighlightsNumerous potential benefits of metformin have been proposed, but its major clinical usage remains limited to treatment of type 2 diabetes and polycystic ovary syndrome (PCOS).Accumulating data indicate that metformin use is associated with adverse effects, notably gastrointestinal issues and vitamin B12 deficiency, and emerging evidence raises concerns about the environmental impacts of its widespread use.Several potential mechanistic targets of metformin have been proposed, but only a limited number are supported by structural evidence.Cutting-edge technologies, such as affinity-based chemoproteomics and structure determination, are being utilized to elucidate direct targets of metformin that are responsible for its beneficial effects on health.AbstractMetformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the importance of elucidating the structural bases of the drug and its direct targets. Ultimately, this review aims to highlight the current state of knowledge regarding metformin and its related emerging discoveries, while also outlining critical future research directions.