2. Academic Validation
  3. Luteolin Induces GPX4-dependent Ferroptosis and Enhances Immune Activation in Colon Cancer

Luteolin Induces GPX4-dependent Ferroptosis and Enhances Immune Activation in Colon Cancer

  • Phytomedicine. 2025 Oct:146:157117. doi: 10.1016/j.phymed.2025.157117.
Qiaochang Cao 1,  Siqi Ding 1,  Xueer Zheng 1,  Hao Li 1,  Lulin Yu 1,  Ying Zhu 1,  Donghai Jiang 2,  Shanming Ruan 3
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, PR China.
  • 2 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, China. Electronic address: jdh8499@zju.edu.cn.
  • 3 The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, PR China. Electronic address: shanmingruan@zcmu.edu.cn.
PMID: 40812220 DOI: 10.1016/j.phymed.2025.157117
Abstract

Background: Ferroptosis is pivotal in colon Cancer progression and immunity. While the natural flavonoid luteolin has Anticancer properties, its Ferroptosis targets and immunomodulatory effects in colon Cancer are unclear.

Purpose: This study aims to validate luteolin's Anticancer efficacy in colon Cancer and elucidate its mechanism involving Ferroptosis induction and antitumor immune activation.

Methods: Integrated WGCNA, machine learning, and functional enrichment techniques to analyze luteolin's potential targets. Comprehensive assays including CCK-8, colony formation, flow cytometry, western blotting, and Reactive Oxygen Species (ROS)/malondialdehyde (MDA)/glutathione (GSH) /FerroOrange profiling, combined with MC38 syngeneic models, were used to investigate luteolin's antiproliferative effects, Glutathione Peroxidase 4 (GPX4) - dependent Ferroptosis induction, and modulation of tumor-infiltrating immune cells. Molecular docking, Cellular Thermal Shift Assay (CETSA), Drug Affinity Responsive Target Stability (DARTS), and surface plasmon resonance (SPR) validated GPX4-luteolin interactions. Anti-CD8 antibody and clodronate liposomes (CLD) immune depletion studies demonstrate that CD8⁺ T cells and macrophages play pivotal roles in activating antitumor immunity.

Results: Bioinformatics indicated luteolin modulates oxidative stress signaling. Luteolin dose-dependently inhibited colon Cancer cell proliferation, reversed by Ferroptosis inhibitor Ferrostatin-1. Luteolin triggered ROS/Fe2+ accumulation, lipid peroxidation, MDA elevation, GSH depletion, and GPX4 downregulation. GPX4 overexpression conferred Ferroptosis resistance, reversed by luteolin. Besides, luteolin directly bound GPX4, enhancing its thermal stability and suppressing pronase E-mediated degradation. In vivo, luteolin exhibited antitumor efficacy through GPX4 downregulation and Ferroptosis induction, synergistically promoting intratumoral M1 macrophage polarization and CD8+ T lymphocyte activation.

Conclusion: Luteolin induces Ferroptosis by directly targeting GPX4, and promotes antitumor immune responses. These findings reveal a novel mechanism underlying luteolin-induced Ferroptosis and provide theoretical support for its immunotherapeutic application in colon Cancer.

Keywords

Cancer immunity; Colon cancer; Ferroptosis; GPX4; Luteolin.

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