Melatonin in the pathogenesis and treatment of metabolic liver diseases

The most prevalent chronic liver diseases are metabolic disorders, which lead to the development of the so-called nonalcoholic fatty liver disease (renamed metabolic dysfunction–associated steatotic liver disease in 2020) with subsequent progression from steatosis, steatohepatitis, and fibrosis to cirrhosis and hepatocellular carcinoma. The disease is more common in developed countries and, according to some estimates, affects approximately one third of the global population. Metabolic dysfunction–associated fatty liver disease is recognized worldwide as the leading cause of chronic liver disease, which remains asymptomatic in many patients and is often diagnosed incidentally. The disease is typically comorbid with obesity, type 2 diabetes mellitus, dyslipidemia, atherosclerosis, and other cardiovascular disorders. Key pathogenetic factors include oxidative stress followed by hepatocyte apoptosis, insulin resistance, cytokine imbalance, mitochondrial dysfunction, impaired autophagy, and other abnormalities that promote the development of inflammatory processes. The disease pathogenesis is complex and not fully understood. Current hypotheses do not fully elucidate the relationships among the individual pathogenetic mechanisms. The management of metabolic dysfunction–associated fatty liver disease is challenging and is primarily aimed at correcting insulin resistance, hepatoprotection, and reducing the risks of progression of associated comorbidities. To date, no unified disease-specific pharmacological strategies have been developed. From a pharmacotherapeutic perspective, melatonin has attracted increasing attention in recent years owing to its capacity to alleviate most of the manifestations of the metabolic syndrome. This review summarizes experimental data and clinical experience regarding the use of melatonin (an indole compound synthesized in the pineal gland) for the correction of metabolic dysfunction of the liver. Melatonin is capable of controlling many physiological processes in hepatic tissue both through activation of its specific receptors and through direct modulation of intracellular pathways, thereby exerting a broad modulatory effect. In experimental models across various animal species, melatonin has demonstrated pronounced hepatoprotective activity. A considerable advantage of melatonin is its ability to alleviate emotional disturbances characteristic of chronic conditions (including anxiety, depressive symptoms, and insomnia). The accumulated evidence has already facilitated the introduction of melatonin into clinical practice and supports further expansion of its applications in hepatic diseases.