**Background:** Protein posttranslational modifications (PTMs) are covalent modifications of proteins that expand the chemical diversity of amino acids beyond genetic encoding. Over 650 types of PTMs have been described, including phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and many others. PTMs dynamically regulate protein conformation, activity, stability, localization, and interactions, thereby controlling cellular processes such as cell cycle, differentiation, metabolism, immunity, and signal transduction. Dysregulation of PTMs is implicated in numerous diseases, including cancers, neurodegenerative disorders, metabolic diseases, and cardiovascular conditions. This review aims to systematically examine the characteristics, regulatory mechanisms, and functions of major PTMs in health and disease, and to discuss therapeutic strategies targeting PTM-associated enzymes.
**Methods:** This is a narrative review that synthesizes findings from a large body of published literature. The authors organized the review by PTM type, covering phosphorylation, acetylation, short-chain fatty acid (SCFA) modifications, long-chain fatty acid modifications, methylation, ubiquitination, SUMOylation, glycosylation, citrullination, carbamylation, redox modifications, and others (ADP-ribosylation, benzoylation, neddylation). For each PTM, the review discusses the enzymes involved (writers, erasers, readers), the chemical process, biological functions, and roles in specific physiological and pathological contexts. The authors also summarize approved and investigational drugs targeting PTM-related enzymes, such as kinase inhibitors, HDAC inhibitors, and PROTACs.
**Key Results:** The review presents extensive evidence linking PTMs to disease. For example, Tau hyperphosphorylation at Ser396/404 is associated with Alzheimer's disease (AD), and plasma P-tau217 and P-tau181 are elevated in AD patients. In cancers, phosphorylation of HK1 at Tyr732 promotes glycolysis and tumor proliferation. Acetylation of H4K16 is involved in transcriptional regulation and cancer. SCFA modifications like lactylation (Kla) are elevated in gastric cancer and promote tumor development. Ubiquitination of p53 by MDM2 leads to its degradation and cancer cell proliferation. SUMOylation of proteins like APP promotes Aβ plaque formation in AD. Citrullination of histones by PAD4 is linked to rheumatoid arthritis and NETosis. Carbamylation of proteins is associated with aging, kidney disease, and atherosclerosis. Redox modifications such as S-nitrosylation regulate cardiovascular function and neurodegeneration. The review also lists numerous approved kinase inhibitors (e.g., imatinib, dasatinib, osimertinib) and HDAC inhibitors (e.g., SAHA) used in cancer and other diseases.
**Clinical Implications:** PTMs offer a rich source of biomarkers and therapeutic targets. Kinase inhibitors are widely used in oncology, and HDAC inhibitors show promise in cancer, neurodegenerative diseases, and metabolic disorders. PROTAC technology enables targeted degradation of disease-associated proteins. Understanding PTM crosstalk and developing multi-omics approaches may lead to new diagnostic and therapeutic strategies. The review emphasizes the need for further research into less-studied PTMs and their roles in large clinical cohorts.