Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence

Abstract

Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N‐acetyl‐5‐methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti‐inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti‐inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma.

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats

“…However, melatonin and cisplatin-cotreated rats exhibited a marked decrease in ovarian TGF-β1 expression and collagen deposition in ovarian tissue. These findings agreed with different studies that reported melatonin administration either intraperitoneally, intravenously, orally, or in drinking water was able to reduce TGF-β expression and decrease tissue and organ fibrosis [49]. Melatonin exerts anti-fibrosis effects by inhibition of epithelial cell injury, including apoptotic and necrotic changes, inflammatory cell infiltration, and the expression of fibrosis-inducing factors, in particular, TGF-β.…”

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

“…San-Miguel, B. et al collated studies over the past 10 years on the anti-fibrotic effects of melatonin and discuss the cellular and molecular mechanisms that prevent progression of liver fibrosis, cirrhosis, and liver cancer [ 79 ]. Two studies using human HSCs cells LX-2 and the primary isolated HSCs showed that the expression levels for liver fibrosis markers (α-SMA, type 1 collagen and TGF-β) decreased after melatonin treatment [ 80 , 81 ].…”

“…Two studies using human HSCs cells LX-2 and the primary isolated HSCs showed that the expression levels for liver fibrosis markers (α-SMA, type 1 collagen and TGF-β) decreased after melatonin treatment [ 80 , 81 ]. Several animal studies showed that melatonin decreased the expression levels for liver fibrosis markers TGF-β, MMP9, and TIMP1 [ 79 ]. Of the three studies discussing the regulation of autophagy by melatonin, two showed a positive effect and one showed a negative effect on autophagy activity [ 79 ].…”

“…Several animal studies showed that melatonin decreased the expression levels for liver fibrosis markers TGF-β, MMP9, and TIMP1 [ 79 ]. Of the three studies discussing the regulation of autophagy by melatonin, two showed a positive effect and one showed a negative effect on autophagy activity [ 79 ].…”

Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management

“…[ 69 ]. Tahan, Akin [ 70 ] found that bile-duct ligation caused levels of collagen, MDA, luminal, and lucigenin to rise while GSH levels fell; however, melatonin had the opposite effect.…”