Betaine as a regulator of metabolism, epigenetics, and cellular osmoprotection: therapeutic implications in cardiometabolic and renal diseases

Betaine, a glycine derivative found in spinach, beets, and whole grains, offers significant pharmacological and nutritional benefits. Researchers are focusing on betaine due to its therapeutic properties and ease of dietary incorporation. The zwitterion betaine is a derivative of N,N,N-trimethylglycine, which is produced during choline metabolism. However, endogenous synthesis of betaine may not always meet the health requirements, and dietary supplementation is needed. Betaine also acts as a methyl donor and an osmolyte and has proven beneficial in treating conditions such as hyper homocysteinemia, inflammation, cardiovascular disorders, and metabolic disorders. Pre-clinical and clinical studies demonstrate its therapeutic effectiveness, supported by safety reports confirming its role in enhancing human health. This review aims to summarize the biochemical, molecular, and therapeutic roles of betaine across multiple disease conditions, with a particular focus on its role in metabolic liver diseases (ALD/MASLD/MASH), cardiovascular dysfunction, diabetes, and renal disorders. Additionally, it highlights betaine's emerging role as an epigenetic regulator and assesses its safety and toxicity profile. Betaine primarily acts as a methyl donor in the one-carbon metabolism pathway, reducing hyperhomocysteinemia and attenuating cardiovascular risk. In hepatic metabolism, betaine modulates lipid homeostasis by regulating key lipogenic transcription factors, contributing to its anti-steatotic and anti-inflammatory effects in MASLD/MASH. Its osmoprotective properties maintain cellular integrity during stress conditions. Furthermore, betaine regulates epigenetic modulations of genes linked to inflammation, fibrosis, and metabolic pathways. Betaine is generally regarded as non-toxic. However, its dose-dependent effects and long-term safety require further analysis, along with detailed evaluations of its multifaceted protective mechanism against disease conditions. Collectively, betaine represents a promising therapeutic candidate with significant translational potential for the treatment of metabolic, cardiovascular/cardiometabolic, and renal diseases.