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Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is one of the major hepatic metabolic disorders that occurs because of the accumulation of lipids in hepatocytes in the form of free fatty acids (FFA) and triglycerides (TG) which become non-alcoholic steatohepatitis (NASH). NOTCH-1 receptors act as novel targets for the development of NAFLD/NASH, where overexpression of NOTCH-1 receptor alters the lipid metabolism in hepatocytes leading to NAFLD. SIRT-1 deacetylates the NOTCH-1 receptor and inhibits NAFLD. Hence, computer-aided drug design (CADD) was used to check the SIRT-1 activation ability of cinnamic sulfonyl hydroxamate derivatives (NMJ 1–8), resveratrol, and vorinostat. SIRT-1 (PDB ID: 5BTR) was docked with eight hydroxamate derivatives and vorinostat using Schrödinger software. Based on binding energy obtained (– 26.31 to – 47.34 kcal/mol), vorinostat, NMJ-2, NMJ-3, NMJ-5 were selected for induced-fit docking (IFD) and results were within – 750.70 to – 753.22 kcal/mol. Qikprop tool was used to analyse the pre pharmacokinetic parameters (ADME analysis) of all hydroxamate compounds. As observed in the molecular dynamic (MD) study, NMJ-2, NMJ-3 were showing acceptable results for activation of SIRT-1. Based on these predictions, in-vivo studies were conducted in CF1 mice, where NMJ-3 showed significant (p < 0.05) changes in lipid profile and anti-oxidant parameters (Catalase, SOD, GSH, nitrite, and LPO) and plasma insulin levels. NMJ-3 treatment also reduced inflammation, fibrosis, and necrosis in liver samples. [ABSTRACT FROM AUTHOR]