The Perspectives of Posttranslational Modifications of Nuclear Proteins in Related Physiology and Diseases Assisted With Multi‐Omics Integrative Analysis and Machine Learning

Many epigenetic drugs lack specificity, which may lead to drug resistance and long-term safety concerns. There is an urgent need to develop more precise nuclear-targeted drugs to reduce adverse reactions and harmful effects. The development of nuclear drugs relies on the exploration of new nuclear targeting mechanisms. This review delves into nuclear protein posttranslational modifications (PTMs), highlighting their roles in nuclear function and influence on cell fate. It showcases the diversity of PTMs, including acetylation, novel acylations, phosphorylation, ubiquitylation, oxidative modifications, itaconation, and citrullination, and differentiates the roles of these modifications between nuclear and non-nuclear proteins. The review partially highlights how nuclear PTMs impact key biological processes, gene expression, and cell function by interacting with cell metabolism. Additionally, it explores the regulatory mechanisms of nuclear PTMs and their implications in diseases such as cancers, and degenerative, metabolic, and inflammatory conditions, suggesting nuclear protein PTMs as potential therapeutic targets. It underscores the need for precise techniques and treatments to study PTMs and introduces the "metabolite-nuclear protein PTM-genome" axis as a novel conceptual framework for future research and therapeutic strategies.