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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Pingyu Liu, 2025. "ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57334-3
    DOI: 10.1038/s41467-025-57334-3
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