Epigenetic regulation encompasses the engagement of adaptive cellular pathways influenced by environmental factors and metabolic changes to modulate gene activity with heritable phenotypic changes without altering the DNA sequences of many target genes. Similar to the Lamarckian concept that the environment can alter individual physiological (heritable) phenotypes, epigenetic alterations produced by an adverse environment and their consequences have been actively studied over the last 2–3 decades (Tikhodeyev, 2020; Zhang, Lu, & Chang, 2020). For instance, epigenetic regulation in the course of normal development and environmental influences have been actively studied, because altered epigenetics are frequently associated with phenotypic changes in cellular physiology often associated with many disease states. Epigenetic regulation can be mediated by the following mechanisms, among others: post-translational modifications (PTMs) of histones and non-histone nuclear proteins, DNA methylation, non-coding RNAs including microRNAs (miRNAs), incorporation of histone variants, nucleosomal positioning, chromatin remodeling, and chromatin accessibility (Gemenetzi & Lotery, 2020; Liberman, Wang, & Greer, 2019). These factors modulate chromatin structure and stability, depending on the cellular context of target cells or environmental stimuli such as intake of alcohol (ethanol) drinking and/or a Western-style high-fat diet (HFD). Reorganization or remodeling of chromatin assembly followed by gene expression change are also known to take place during normal development or regeneration after liver injury, as described (Jia, Lin, & Wang, 2023; Wang et al., 2020).

Numerous expert scientists have published review articles on epigenetic regulation in normal development and many disease states affected by aging, genetic risk, and environmental factors (Bellanti & Vendemiale, 2021; Cavalli & Heard, 2019; Feinberg, 2018; Li, Barrero, Merali, & Praticò, 2017; Park, Friso, & Choi, 2012). These reviews have described epigenetic regulation in cancer, cardiovascular diseases, diabetes, obesity and metabolic syndromes, liver diseases as well as neurological and other disorders. In the current review, we highlight the roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1)-mediated oxidative alcohol metabolism and oxidative/nitrative stress in promoting various PTMs of nuclear proteins and epigenetic regulation in alcohol-associated liver disease (ALD) and other pathological conditions associated with alcohol use disorder (AUD). In addition, we specifically focus on the contributing roles of many different types of PTMs, including less-characterized modifications of histone and non-histone proteins in regulating epigenetic changes, instead of reviewing widely accepted reports. Based on our mechanistic understanding, we also describe the potential challenges and research opportunities for basic and translational research in studying genetic and epigenetic regulation.