2. Academic Validation
  3. NAD+ Metabolism Reprogramming Drives SIRT1-Dependent Deacetylation Inducing PD-L1 Nuclear Localization in Cervical Cancer

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

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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