Licochalcone C suppresses gastric cancer progression and enhances 5-FU chemosensitivity by targeting RAC3-mediated PI3K-AKT-mTOR signaling

  • Phytomedicine. 2026 Oct:160:158634. doi: 10.1016/j.phymed.2026.158634.
Qingshui Wang  1 ,  Yiping Lu  1 ,  Yuluo Chen  2 ,  Jinxiu Zhou  2 ,  Kejia Guo  1 ,  Yifei Liu  1 ,  Yimin Huang  1 ,  Yi Zheng  1 ,  Hao Li  1 ,  Yan Ye  3 ,  Jia Lin  1 ,  Minghan Huang  4 ,  Fangqin Xue  5 ,  Yao Lin  6
Affiliations
  • 1. The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, College of Integrative Medicine, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China.
  • 2. College of life science, Fujian Normal University, Fuzhou, Fujian, China.
  • 3. Ganzhou Key Laboratory of Molecular Medicine, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, Jiangxi, China.
  • 4. Department of Gastroenterology, the second people's Hospital affiliated to Fujian University of traditional Chinese Medicine, Fuzhou, Fujian, China. Electronic address: [email protected].
  • 5. Department of Gastrointestinal Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, China.. Electronic address: [email protected].
  • 6. The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, College of Integrative Medicine, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. Electronic address: [email protected].
PMID: 42537463 DOI: 10.1016/j.phymed.2026.158634
Abstract

Background: Gastric Cancer remains a leading cause of cancer-related mortality worldwide, with limited sensitivity to 5-fluorouracil (5-FU) representing a major obstacle to effective chemotherapy. Licochalcones, bioactive Chalcones derived from licorice, have demonstrated broad-spectrum Anticancer activities, yet the role of Licochalcone C in enhancing 5-FU sensitivity in Gastric Cancer remains unexplored.

Purpose: This study aimed to investigate the antitumor effects of Licochalcone C on Gastric Cancer and evaluate its potential to enhance 5-FU chemosensitivity, along with elucidating the underlying molecular mechanisms.

Study design: The antitumor and chemosensitizing effects of Licochalcone C were systematically evaluated using human Gastric Cancer cell lines, patient-derived organoids, clinical specimens, and a mouse xenograft model.

Methods: Cell proliferation, colony formation, migration, invasion, and cell cycle distribution were assessed by standard assays. Biotin-labeled Licochalcone C pull-down with mass spectrometry, molecular docking, cellular thermal shift assay, and co-immunoprecipitation were employed for target identification. Western blot and transcriptomic analyses defined the signaling mechanisms.

Results: Licochalcone C inhibited Gastric Cancer cell proliferation, migration, and invasion while inducing G1 arrest, and markedly enhanced 5-FU sensitivity in cell lines, organoids, and xenograft models. Mechanistically, Licochalcone C directly bound RAC3, suppressing the RAC3-mediated PI3K-AKT-mTOR pathway and downregulating P-glycoprotein. Clinically, RAC3 overexpression correlated with advanced stage, poor survival, and unfavorable chemotherapy response.

Conclusion: Licochalcone C functions as a RAC3-targeting chemosensitizer that enhances 5-FU efficacy by inhibiting PI3K-AKT-mTOR signaling and P-glycoprotein expression, supporting its development as a therapeutic Adjuvant for Gastric Cancer.

Keywords
5-FU; Cell cycle; Gastric cancer; Licochalcone C; RAC3.
Products