Targeting gut-derived NETosis: A paradigm shift in understanding metformin's therapeutic action

Metformin remains the most widely prescribed drug for diabetes management, yet recent studies have explored additional benefits, whose mechanisms are not completely understood. Recent research has highlighted the central role of the intestine in mediating metformin's therapeutic effects, involving interactions with the gut microbiota, intestinal epithelial cells, and the immune system. Among its various properties, metformin also exhibits immunomodulatory activity, drawing growing attention to its impact on neutrophil function. In particular, the excessive formation of neutrophil extracellular traps (NETs) and the process of NETosis have been linked to diabetes and its complications. Emerging evidence suggests that NETosis is influenced by alterations in gut microbiota composition and may itself contribute to metabolic dysregulation. This review explores intestinal NETosis as a novel and promising target of metformin, emphasizing its potential therapeutic relevance and the need for further investigation. A deeper understanding of these molecular pathways is essential to explore new therapeutic applications, guide the development of more personalized therapies that minimize adverse effects, and inspire next-generation drugs that improve metformin's efficacy.