ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

Li Yang, Jianwei You, Xincheng Yang, Ruishu Jiao, Jie Xu, Yue Zhang, Wen Mi, Lingzhi Zhu, Youqiong Ye, Ruobing Ren, Delin Min, Meilin Tang, Li Chen, Fuming Li and Pingyu Liu ()
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Li Yang: Fudan University
Jianwei You: Fudan University
Xincheng Yang: Fudan University
Ruishu Jiao: Shanghai Jiao Tong University School of Medicine
Jie Xu: Fudan University
Yue Zhang: Fudan University
Wen Mi: Fudan University
Lingzhi Zhu: Fudan University
Youqiong Ye: Shanghai Jiao Tong University School of Medicine
Ruobing Ren: Fudan University
Delin Min: Fudan University
Meilin Tang: Fudan University
Li Chen: Fudan University
Fuming Li: Fudan University
Pingyu Liu: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.

Date: 2025
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DOI: 10.1038/s41467-025-57334-3

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