乙酰化修饰在特发性肺纤维化中的研究进展

Research Progress of Protein Acetylation in Idiopathic Pulmonary Fibrosis

摘要: 特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)的发病机制与蛋白质乙酰化修饰失衡相关。细胞骨架相关蛋白乙酰化异常通过调控微管/微丝稳定性促进肌成纤维细胞活化及上皮细胞凋亡；SIRT/HDAC异常可引起线粒体功能障碍加剧氧化应激与代谢紊乱。巨噬细胞极化失衡通过乙酰化介导炎症–纤维化级联反应。肺泡上皮细胞中SIRT家族通过增强抗氧化能力维持再生功能，而成纤维细胞通过HAT/HDAC/SIRT调控网络激活TGF-β信号通路，驱动细胞外基质过度沉积。靶向HDAC抑制剂和SIRT激活剂的治疗策略需进一步优化其靶向性与安全性。未来研究应重点鉴定IPF发生发展过程中的关键乙酰化位点及其调控网络，并结合单细胞蛋白质组学等新技术解析不同细胞亚群的乙酰化特征，以期为精准干预策略的开发提供新的理论依据。

Abstract: The pathogenesis of idiopathic pulmonary fibrosis (IPF) is associated with dysregulated protein acetylation modification. Aberrant acetylation of cytoskeleton-related proteins facilitates myofibroblast activation and alveolar epithelial cell apoptosis by modulating the stability of microtubules and microfilaments. Abnormalities in sirtuin (SIRT)/histone deacetylase (HDAC) trigger mitochondrial dysfunction, thereby exacerbating oxidative stress and metabolic disorders. Imbalanced macrophage polarization initiates an inflammation-fibrosis cascade mediated by acetylation. Within alveolar epithelial cells, the SIRT family preserves regenerative capacity via enhanced antioxidant activity, whereas fibroblasts activate the TGF-β signaling pathway through the regulatory network consisting of histone acetyltransferase (HAT)/HDAC/SIRT, leading to excessive extracellular matrix deposition. Therapeutic strategies targeting HDAC inhibitors and SIRT activators require further optimization in targeting specificity and safety. Future research should focus on identifying critical acetylation sites and elucidating their regulatory networks during the development and progression of IPF. Furthermore, advanced technologies such as single-cell proteomics may help characterize cell type-specific acetylation signatures, thereby providing novel mechanistic insights for the development of precise therapeutic interventions.