Archive > Volume 18 Issue 1 > 2026,18(1):110-123. DOI:https://doi.org/10.1016/j.chmed.2025.02.009 Prev Next

蛋白S-棕榈酰化：糖尿病并发症的病理机制和新的治疗靶点

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Protein S-acylation: Pathological mechanisms and novel therapeutic targets for diabetic complications

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    摘要:
    糖尿病累及的多器官并发症严重威胁人类生命健康，已成为全球重点关注的重大的公共卫生问题。不幸的是，受限于对其复杂病理机制的有限了解，目前针对糖尿病并发症的临床防治策略仍处于婴儿阶段。众所周知，脂质代谢紊乱是糖尿病的特征性病理因素，但其驱动多器官并发症进展的详细分子机制仍然模糊。蛋白质S-酰化（通常称为S-棕榈酰化）是一种可逆的脂化修饰，通过棕榈酰化酶和去棕榈酰化酶使脂肪酸与蛋白质特定的半胱氨酸残基可逆结合，参与了癌症、神经系统疾病、代谢综合征等多种复杂性疾病病理进展。值得注意的是，近期的研究表明蛋白质S-棕榈酰化驱动了糖尿病及其多种并发症的进展，并且靶向干预蛋白质S-棕榈酰化过程明显缓解了糖尿病及其并发症的进展，表明蛋白质S-棕榈酰化可能是糖尿病并发症共性的病理环节和干预靶点。因此，本综述系统梳理了蛋白质S-棕榈酰化对糖尿病及其并发症进展的贡献，并且总结了糖尿病环境对S-棕榈酰化调控酶的影响，同时深度剖析了当前靶向S-棕榈酰化的药物、措施和挑战。最后展望了靶向棕榈酰化修饰防治糖尿病及其并发症的可及性和未来深入研究的重点，以期为未来靶向蛋白质S-棕榈酰化防治糖尿病及其多器官并发症的新策略提供全面深入的参考和依据。

    Abstract:
    Diabetes involves multi-organ complications that seriously threaten human life and health, and has become a major public health problem of global concern. Unfortunately, clinical management strategies for diabetic complications are still in their ‘‘infancy”, restricted by a limited understanding of their complex pathological mechanism. As is well established, lipid metabolism disorder is the characteristic pathological factors of diabetes, but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure. Protein S-acylation (often referred to as S-palmitoylation) is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine (Cys) residues through palmitoyl acyl transferases (PATs, also known as DHHCs) and deacylation enzymes, which is involved in the pathological progression of a variety of complex diseases such as cancer, neurological disorders and metabolic syndrome. Notably, recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications, and targeted intervention in the protein Sacylation process significantly alleviates the progression of diabetes and its complications, suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications. Therefore, this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications, summarizes the influence of the diabetic environment on S-acylation related enzymes, as well as providing an in-depth analysis of current drugs, measures, and challenges in targeting S-acylation. Finally, the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned, with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.

    关键词:
    糖尿病;糖尿病并发症;S-酰化;S-棕榈酰化;靶向治疗

    Keywords:


    Project Supported:
    This work is supported by National Natural Science Foundation of China (No. 82304909), National Natural Science Foundation of China (No. 82174112), Tianjin Science and Technology Innovation Base Construction (No. 24ZYJDSY00280).

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