Ginsenoside Rb2 promotes p62-mediated LDHA autophagic degradation to inhibit H3K18la-dependent PD-L1 transcription in cervical cancer.

Authors

Xingwei Wang, Ziyue Zhang, Mei Chen, Liu Luo, Ru Sun, Chen Chen, Minmin Yu

Published in

Frontiers in oncology. Volume 16. Pages 1962784. Epub Sep 28, 2026.

Abstract

Ginsenoside Rb2 has demonstrated antitumor activity in multiple malignancies, yet its role in cervical cancer and the underlying mechanism remain unclear. This study investigated the effects of Rb2 on cervical cancer progression and explored whether metabolic reprogramming contributes to PD-L1 regulation.
Cell proliferation, migration, invasion, glycolytic activity, lactate production, histone lactylation, and PD-L1 expression were evaluated in cervical cancer cells using CCK-8, EdU, colony formation, wound-healing, Transwell, Seahorse analysis, RT-qPCR, western blotting, flow cytometry, and ChIP-qPCR. LDHA regulation was examined by protein and mRNA stability assays, pharmacological inhibition, lysosome immunoprecipitation, gain- and loss-of-function studies, co-immunoprecipitation, molecular docking, and biotinylated Rb2 pull-down assays. T-cell function was assessed by Jurkat T-cell-tumor cell co-culture and IL-2 ELISA. Xenograft models and clinical samples were used for validation.
Rb2 significantly inhibited cervical cancer cell proliferation, migration, invasion, and xenograft tumor growth, reducing HeLa and SiHa cell viability by approximately 23.4% and 25.7%, respectively. Rb2 selectively downregulated PD-L1 and suppressed glycolysis and lactate production, with reduced H3K18la/H4K12la lactylation at the PD-L1 promoter. LDHA was the primary glycolytic enzyme reduced by Rb2, without changes in its mRNA. Rb2 decreased LDHA protein stability and promoted its autophagy-lysosome-dependent degradation, with p62 required and the p62-LDHA interaction enhanced by Rb2. Rb2-pretreated tumor cells restored IL-2 production by co-cultured Jurkat T cells, whereas LDHA overexpression reversed this effect. LDHA overexpression partially rescued Rb2's effects, and LDHA correlated positively with PD-L1 in cervical cancer tissues.
Rb2 suppresses cervical cancer progression by promoting p62-dependent autophagic degradation of LDHA, thereby inhibiting glycolysis-associated H3K18la and PD-L1 transcription. These findings reveal a p62/LDHA/H3K18la/PD-L1 signaling axis through which Rb2 exerts its antitumor effects.

PMID:
42865485
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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