Therapeutic potential of 5-aminolevulinic acid in metabolic disorders: Current insights and future directions.

5-Aminolevulinic acid (5-ALA) is an essential compound in the biosynthesis of heme, playing a critical role in various physiological processes within the human body. This review provides the thorough analysis of the latest research on the molecular mechanisms and potential therapeutic benefits of 5-ALA in managing metabolic disorders. The ability of 5-ALA to influence immune response and inflammation, oxidative/nitrosative stress, antioxidant system, mitochondrial functions, as well as carbohydrate and lipid metabolism, is mediated by molecular mechanisms associated with the suppression of the transcription factor NF-κB signaling pathway, activation of the transcription factor Nrf2/heme oxygenase-1 (HO-1) system leading to the formation of heme-derived reaction products (carbon monoxide, ferrous iron, biliverdin, and bilirubin), which may contribute to HO-1-dependent cytoprotection through antioxidant and immunomodulatory effects. Additionally, it regulates the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, cytochrome oxidase subunit IV, uncoupling proteins UCP1 and UCP2, glucose transporters GLUT1 and GLUT2, and sterol regulatory element-binding protein 1c in relevant tissues. Randomized controlled trials have confirmed the effects of 5-ALA on glucose control in both prediabetic and diabetic patients, noting its safety and tolerability, as well as the safety of its combined use with oral hypoglycemic agents. Only minor side effects have been reported. However, the impact of 5-ALA on markers of systemic inflammation, oxidative and nitrosative stress, and dyslipidemia was not evaluated in these studies. At the same time, preparations of 5-ALA may potentially be effective not only in the treatment of prediabetes and type 2 diabetes mellitus (T2DM), but also in other conditions associated with systemic inflammation, oxidative or nitrosative stress, mitochondrial dysfunction, as well as disorders of carbohydrate and lipid metabolism. It has been concluded that the promising advancement of formulations containing 5-ALA may pave the way for new strategies in preventing and treating these diseases, with subsequent preclinical and clinical trials likely to follow.