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ARTICLE

Regulation of Histone Emulsification by HPDL via LDHA/LDHB Promotes EC Cell Proliferation

Yan Wang1,#, Jialei Zhu2,#, Shiyang Wei3,4,#, Lijie Jin1, Zhanqiu Liu1, Jie Xu1, Nana Yang1, Xuefeng Jiang4, Caizhi Wang1,*, Lingling Wang1,*
1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
2 Department of Gynecology, Huaiyuan County Hospital of Traditional Chinese Medicine, Bengbu, China
3 Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Qingxiu District, Nanning, China
4 Department of Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China
* Corresponding Author: Caizhi Wang. Email: email; Lingling Wang. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: New Advance in Gynecologic Oncology)

Oncology Research https://doi.org/10.32604/or.2026.068833

Received 07 June 2025; Accepted 29 December 2025; Published online 10 March 2026

Abstract

Background: The role of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) in endometrial cancer (EC) progression remains poorly understood, particularly its involvement in metabolic-epigenetic crosstalk via lactate-driven histone lactylation. This study aimed to investigate HPDL’s mechanistic contribution to EC pathogenesis. Methods: Stable HPDL-overexpressing and knockdown EC cell lines (HEC-1-B and AN3CA) were generated using lentiviral vectors. Functional assays (proliferation, migration, invasion), subcutaneous xenograft models in BALB/c nude mice, and molecular analyses were conducted. Lactate levels, Pan-lysine lactylation (pan-kla), histone H3K18 lactylation (H3K18la), and effects of sodium oxamate (lactate modulator) were assessed. Lactate Dehydrogenase A/Lactate Dehydrogenase B (LDHA/LDHB) knockdown, promoter activity assays, and chromatin immunoprecipitation (ChIP) were performed to evaluate H3K18la occupancy at LDHA/LDHB promoters. Results: HPDL knockdown reduced intracellular lactate, Pan-Kla, and H3K18la levels, while overexpression elevated these markers. Sodium oxamate amplified lactate and lactylation in HPDL-overexpressing cells but suppressed histone lactylation independently of HPDL. LDHA/LDHB knockdown diminished lactylation, repressed HPDL expression, and inhibited promoter activity. ChIP revealed H3K18la enrichment at LDHA/LDHB promoters in HPDL-overexpressing cells and reduced occupancy in knockdown models. HPDL enhanced EC cell proliferation, migration, and invasion in vitro. In vivo, HPDL-overexpressing xenografts exhibited accelerated tumor growth and larger volumes compared to controls. Conclusions: HPDL regulates histone lactylation via LDHA/LDHB and promotes the proliferation of EC cells.

Keywords

Endometrial cancer; histone lactylation; 4-hydroxyphenylpyruvate dioxygenase-like protein; lactate dehydrogenase A/B; cell proliferation

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