Ubiquitination and Acetylation in Cellular Senescence: Mechanisms, Crosstalk, and Therapeutic Implications

作者：Mengjiao Yu, Jiaxin Liu, Weiwei Shi, Mengna Jiang, Haihui Hou, Yufei Xue, Haotian Xu, Luyao Jiang, Hanrui Liu, Demin Cheng, Xinyuan Zhao · 发表于：The FASEB Journal · 年份：2025 · DOI：10.1096/fj.202503324r · 被引用次数：5 · 研究领域：Telomeres, Telomerase, and Senescence、Sirtuins and Resveratrol in Medicine、Ubiquitin and proteasome pathways

Cellular senescence represents a fundamental molecular basis underlying the disruption of tissue homeostasis and the onset of age-related diseases, in which post-translational modifications (PTMs) play pivotal roles in orchestrating senescence programs. This review focuses on two major lysine modifications-ubiquitination and acetylation. We first provide an overview of the concept and phenotypic features of cellular senescence, followed by a detailed discussion of the ubiquitination cascade (E1-E2-E3) and the functional consequences of distinct ubiquitin chain types (e.g., K48, K63) on protein fate and signaling. We further summarize the ubiquitination-mediated regulation of canonical senescence regulators (p53, p21, p16) and pathways involved in autophagy and cellular homeostasis, DNA damage response, and genome stability. Subsequently, we highlight the role of acetylation in senescence, introducing acetyltransferases (e.g., CBP/p300) and deacetylases (HDACs, SIRTs) and their substrate spectra, with emphasis on how acetylation orchestrates cell cycle progression, DNA repair, inflammation and SASP, mitochondrial homeostasis, and autophagy. The crosstalk between ubiquitination and acetylation is also discussed, as these modifications compete for lysine residues and form cascade effects through the interplay of E3 ligases, deubiquitinases, acetyltransferases, and deacetylases, thereby shaping senescence networks. Finally, we summarize current pharmacological advances targeting ...