Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes. Among these, protein lipidations which refer to lipid attachment to proteins are prominent, which primarily encompassing five types including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor and cholesterylation. Lipid attachment to proteins plays an essential role in the regulation of protein trafficking, localisation, stability, conformation, interactions and signal transduction by enhancing hydrophobicity. Accumulating evidence from genetic, structural, and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases. Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation, and several agents have been developed and tested in preclinical and clinical studies, some of which, such as asciminib and lonafarnib are FDA-approved for therapeutic use, indicating that targeting protein lipidations represents a promising therapeutic strategy. Here, we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types, outline the impact of protein lipidations on physiology and disease, and highlight potential therapeutic targets and clinical research progress, aiming to provide a comprehensive reference for future protein lipidation research.

翻译后修饰增加了蛋白质的复杂性和功能多样性，以响应复杂的外部刺激和内部变化。其中，蛋白质脂化是指脂质附着在蛋白质上的作用最为突出，主要包括S-棕榈酰化、N-肉豆蔻酰化、S-异戊二烯化、糖基磷脂酰肌醇（GPI）锚定和胆固醇化五种类型。蛋白质上的脂质附着通过增强疏水性在蛋白质运输、定位、稳定性、构象、相互作用和信号转导的调节中发挥重要作用。来自遗传、结构和生物医学研究的不断积累的证据一致表明，蛋白质脂化在广泛生理功能的调节中至关重要，并且与多种疾病有着千丝万缕的联系。数十年的专门研究推动了多种针对蛋白质脂化的药物的开发，并且已经开发出多种药物并在临床前和临床研究中进行了测试，其中一些药物（如阿西米尼和洛那法尼）已获得 FDA 批准用于治疗用途，这表明靶向蛋白质脂化代表了一种有前途的治疗策略。在此，我们全面回顾了已知的各种蛋白质脂化类型的调节酶和催化机制，概述了蛋白质脂化对生理和疾病的影响，并重点介绍了潜在的治疗靶点和临床研究进展，旨在为未来蛋白质脂化研究提供全面的参考。