2. Academic Validation
  3. Gambogic acid induces ferroptosis and suppresses colorectal cancer progression by modulating the m6A modification of p62

Gambogic acid induces ferroptosis and suppresses colorectal cancer progression by modulating the m6A modification of p62

  • Cell Signal. 2025 Nov:135:112024. doi: 10.1016/j.cellsig.2025.112024.
Jinshuang Wang 1,  Jun Deng 2,  Baihan Sun 3,  Guanglei Qiao 4,  Jing Yang 5,  Zhen Gao 5,  Qi Zhang 5,  Min Dong 5,  Pengfei Qu 6,  Zhenxin Wang 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, The First Affiliated Hospital of Soochow University,899 Pinghai Road, Suzhou, Jiangsu 215006, China; Department of Oncology, Xuzhou Hospital of Traditional Chinese Medicine, Xuzhou, Jiangsu 221018, China.
  • 2 Department of Medical Oncology, The First Affiliated Hospital of Soochow University,899 Pinghai Road, Suzhou, Jiangsu 215006, China; Department of Early ClinicalTrail Center, The Affiliated Cancer Hospital of Xiangya School of Medicine CentralSouth University/Hunan Cancer Hospital, Changsha, Hunan 410013, China.
  • 3 Department of Orthopedics, Xuzhou Hospital of Traditional Chinese Medicine, Xuzhou, Jiangsu 221018, China.
  • 4 Department of Medical Oncology, The First Affiliated Hospital of Soochow University,899 Pinghai Road, Suzhou, Jiangsu 215006, China.
  • 5 Department of Oncology, Xuzhou Hospital of Traditional Chinese Medicine, Xuzhou, Jiangsu 221018, China.
  • 6 Department of Gastroenterology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China. Electronic address: qupengfei1678@163.com.
  • 7 Department of Medical Oncology, The First Affiliated Hospital of Soochow University,899 Pinghai Road, Suzhou, Jiangsu 215006, China. Electronic address: zhenxw316@163.com.
PMID: 40721064 DOI: 10.1016/j.cellsig.2025.112024
Abstract

Ferroptosis has emerged as a novel therapeutic target in Cancer treatment. RNA N6-methyladenosine (m6A) methylation, plays a critical role in regulating Ferroptosis and mediating tumor progression and therapy resistance. Gambogic acid (GA), a plant-derived compound with potent antitumor activity, was investigated for its role in inducing Ferroptosis in colorectal Cancer (CRC). In this study, we demonstrated that GA induces Ferroptosis in CRC cells, as evidenced by increased Fe2+, reactive ROS, and MDA levels, alongside reduced GSH levels. These effects were reversed by Ferroptosis inhibitors, iron chelators and Autophagy inhibitors. Mechanistically, GA reduced global m6A contents by downregulating methyltransferase3 (METTL3) expression. Overexpression of METTL3 reversed GA-induced Ferroptosis and associated biochemical changes. Importantly, METTL3-mediated m6A modification enhanced the stability of p62 mRNA in an IGF2BP1-dependent manner. GA decreased METTL3 protein stability through the ubiquitin-proteasomal degradation. Collectively, these findings reveal that GA induces Ferroptosis in CRC by modulating METTL3-mediated m6A modification of p62, connecting RNA Epigenetics to autophagy-ferroptosis crosstalk. This study provides novel insights into the therapeutic potential of targeting the METTL3/p62 axis for ferroptosis-based Cancer therapy.

Keywords

Colorectal cancer; Ferroptosis; Gambogic acid; METTL3.

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