2. Academic Validation
  3. PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity

PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity

  • Cancer Lett. 2025 Oct 10:630:217901. doi: 10.1016/j.canlet.2025.217901.
Xue Wang 1,  Ye Li 2,  Yanxin Tang 2,  Zhiyu Liu 2,  Yuan Liu 2,  Xueli Fu 2,  Shiman Guo 2,  Jiaqi Ma 2,  Fangyuan Ma 2,  Zhitu Zhu 3,  Weiying Zhang 4,  Lihong Ye 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China; Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, PR China.
  • 2 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
  • 3 Liaoning Provincial Key Laboratory of Clinical Oncology Metabonomics, Institute of Clinical Bioinformatics, Cancer Center of Jinzhou Medical University, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, PR China.
  • 4 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China. Electronic address: zhwybao@nankai.edu.cn.
  • 5 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China. Electronic address: yelihong@nankai.edu.cn.
PMID: 40614853 DOI: 10.1016/j.canlet.2025.217901
Abstract

Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is overexpressed in several malignancies. The newly identified protein posttranslational modification lactylation, occurring on lysine residues, is extensively involved in various biological processes. However, PD-L1 lactylation and its role in tumorigenesis remain unclear. In this study, we discover that lactylation of PD-L1 suppresses liver Cancer growth by inhibiting Cholesterol synthesis. Acetyltransferase E1A-binding protein p300 (p300) catalyzes the lactylation of PD-L1 at the lysine 189 residue (K189). Histone deacetylase 2-dependent delactylation of PD-L1 K189 promotes vimentin-mediated nuclear translocation of PD-L1. Functionally, PD-L1 K189 delactylation accelerates liver Cancer growth both in vitro and in vivo by facilitating Cholesterol production. Clinically, an antibody against PD-L1 K189 lactylation reveals that PD-L1 delactylation is positively associated with the progression of liver Cancer histological grade. Mechanistically, PD-L1 K189 delactylation upregulates SQLE, a rate-limiting enzyme in Cholesterol biosynthesis, by increasing SQLE transcription activity via the transcription factor YY1. Therefore, our findings demonstrate that lactylation-dependent regulation of PD-L1 promotes liver Cancer growth.

Keywords

Cholesterol biosynthesis; Lactylation; Liver cancer; Nuclear translocation; PD-L1.

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