NAD+ Metabolism Reprogramming Drives SIRT1-Dependent Deacetylation Inducing PD-L1 Nuclear Localization in Cervical Cancer

  • Adv Sci (Weinh). 2025 Feb 23:e2412109. doi: 10.1002/advs.202412109.
Xinyi Lu  1  2 ,  Pingping Jin  1 ,  Qianyun Tang  1 ,  Min Zhou  1 ,  Hanjie Xu  1 ,  Chen Su  1 ,  Lei Wang  2  3 ,  Feng Xu  1 ,  Min Zhao  1 ,  Yongxiang Yin  1 ,  Jinqiu Zhang  1 ,  Zhen Jia  4 ,  Xinrui Peng  1 ,  Jie Zhou  1 ,  Lu Wang  1 ,  Yan Chen  1 ,  Min Wang  2 ,  Min Yang  5 ,  Daozhen Chen  1  2  4 ,  Yu Chen  1  2
Affiliations
  • 1. Affiliated Women's Hospital of Jiangnan University, Jiangnan University, Jiangsu, 214002, China.
  • 2. Wuxi Medical Center, Nanjing Medical University, Jiangsu, 214023, China.
  • 3. Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Jiangsu, 214002, China.
  • 4. Department of Laboratory, Haidong Second People's Hospital, Haidong, 810699, China.
  • 5. Molecular Imaging Centre, Jiangsu Institute of Nuclear Medicine, Jiangsu, 214063, China.
PMID: 39988985 DOI: 10.1002/advs.202412109
Abstract

Cervical Cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD+) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of Immune Checkpoint Proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.

Keywords
NAD+ metabolism; PD‐L1, SIRT1; acetyl‐proteomics; cervical cancer; immunotherapy resistance.
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