2. Academic Validation
  3. Icariin-curcumol inhibits histone H3K18 lactylation and FOXM1 expression to enhance the sensitivity of prostate cancer cells to docetaxel

Icariin-curcumol inhibits histone H3K18 lactylation and FOXM1 expression to enhance the sensitivity of prostate cancer cells to docetaxel

  • Cancer Cell Int. 2025 Nov 25;25(1):423. doi: 10.1186/s12935-025-03927-3.
Wen Sheng # 1,  Yingqiu Li # 2,  Tao Tan 1,  Xincheng Yu 1,  Xuxi Huang 1,  Lingyi Li 1,  Canying Zhang 1,  Yalin Chen 1,  Lumei Liu 3 4,  Min Feng 1,  Haitao Dang 1,  Qinghu He 1 3 4,  Wenjing Xu 5
Affiliations

Affiliations

  • 1 School of Traditional Chinese Medicine, Hunan University of Medicine, Huaihua, 418000, China.
  • 2 Medical School, Hunan University of Chinese Medicine, Changsha, 410208, China.
  • 3 School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China.
  • 4 Andrology Laboratory, Hunan University of Chinese Medicine, Changsha, 410208, China.
  • 5 Department of Dermatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, No. 95 Shaoshan Middle Road, Yuhua District, Changsha, 410021, China. [email protected].
  • # Contributed equally.
PMID: 41291725 DOI: 10.1186/s12935-025-03927-3
Abstract

Background: Histone lactylation has emerged as an epigenetic driver of tumor chemoresistance. Our prior work identified the phytochemical combination icariin-curcumol (Ica-Cur) as a potential therapeutic agent against docetaxel (DTX)-resistant prostate Cancer (PCa). This study aimed to investigate the mechanistic link between histone lactylation and DTX resistance in PCa, and evaluates Ica-Cur's regulatory role in this process.

Methods: DTX-resistant LNCaP/R cells were generated from parental LNCaP PCa cells. Xenograft models were established in BALB/c nude mice using both cell lines. Interventions included pharmacological modulation of glycolysis (sodium lactate [Nala], a glycolysis activator and 2-deoxy-D-glucose [2-DG], a glycolysis inhibitor) and genetic silencing of forkhead box M1 (FOXM1) via lentiviral constructs (sh-FOXM1). The enrichment of histone H3K18 lactylation (H3K18la) at the FOXM1 promoter was validated. Tumor growth, lactate levels, Lactate Dehydrogenase (LDH) activity, proliferation, and Apoptosis were systematically analyzed.

Results: Resistant LNCaP/R models exhibited significant upregulation of H3K18la and FOXM1 compared to controls. Nala increased lactate production, enhanced H3K18la deposition, and stimulated proliferation while suppressing Apoptosis. Conversely, 2-DG reduced H3K18la deposition and inhibited proliferation. FOXM1 expression was directly regulated by H3K18la, with sh-FOXM1 reducing LDH activity, inhibiting proliferation, and inducing Apoptosis. Ica-Cur restored DTX sensitivity by suppressing H3K18la and FOXM1 expression.

Conclusion: These findings identify H3K18la-mediated FOXM1 activation as a novel mechanism underlying DTX resistance in PCa. Ica-Cur may represent a promising therapeutic agent by targeting lactylation-dependent epigenetic regulation and FOXM1-driven transcriptional activity, supporting its clinical potential for overcoming chemoresistance.

Keywords

Chemotherapy resistance; FOXM1; Histone lactylation; Prostate cancer.

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