2. Academic Validation
  3. Arnicolide C induces ROS-mediated modulation of PI3K/Akt and MAPK pathways to suppress MYC in hepatocellular carcinoma

Arnicolide C induces ROS-mediated modulation of PI3K/Akt and MAPK pathways to suppress MYC in hepatocellular carcinoma

  • Phytomedicine. 2025 Oct 20:148:157423. doi: 10.1016/j.phymed.2025.157423.
Chi Teng 1,  Jia-Wen Chen 1,  Li-Sha Shen 2,  Zesi Lin 3,  Yu-Shan Lin 4,  Wan-Ying He 5,  Zi-Han Yuan 5,  Ze-Xuan Yang 5,  Yu-Xin Liu 5,  Yu-Bing Lei 5,  Hongyang Zhang 6,  Sibao Chen 7,  Guo-Qing Chen 8
Affiliations

Affiliations

  • 1 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.
  • 2 Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China.
  • 3 Southern Medical University Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Southern Medical University, Guangzhou 510315, China.
  • 4 The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.
  • 5 College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
  • 6 The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China; Department of Applied Biology and Chemical Technology and Research Institute for Smart Energy, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China. Electronic address: hongyang.zhang@polyu.edu.hk.
  • 7 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China. Electronic address: sibao.chen@polyu.edu.hk.
  • 8 College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China. Electronic address: chenguoqing@sztu.edu.cn.
PMID: 41138574 DOI: 10.1016/j.phymed.2025.157423
Abstract

Background: The urgent need for more effective therapies for hepatocellular carcinoma (HCC), an aggressive and lethal liver Cancer, has prompted the search for novel compounds with distinct mechanisms of action. Targeting Reactive Oxygen Species (ROS) has emerged as a promising Anticancer strategy, particularly for natural products that modulate redox homeostasis. Arnicolide C (AC), a sesquiterpene lactone from Centipeda minima, has demonstrated potential Anticancer activity, but its efficacy against HCC and the underlying mechanisms remain unclear.

Methods: We assessed the effects of AC on HCC cell proliferation, Apoptosis, and metastasis through a series of in vitro assays. Its antitumor efficacy was further validated in a xenograft mouse model. RNA-seq-based bioinformatics analysis was conducted to explore potential molecular targets and pathways. ROS generation by AC was evaluated using both chemical and cellular assays. The role of ROS in mediating AC's effects was investigated in vitro and in vivo using the ROS scavenger N-acetylcysteine (NAC).

Results: AC markedly inhibited HCC cell proliferation, triggered Apoptosis, and suppressed metastatic behaviors. Notably, AC reduced tumor growth without overt toxicity in vivo. Mechanistically, AC downregulated the oncogene MYC by modulating the PI3K/Akt and MAPK pathways. Importantly, AC induced ROS accumulation in HCC cells, and NAC abrogated its antitumor effects and reversed the suppression of MYC and related signaling pathways.

Conclusion: AC exerts potent anti-HCC activity via ROS-mediated modulation of PI3K/Akt and MAPK signaling, resulting in MYC downregulation. These findings support AC as a promising redox-targeting therapeutic agent for HCC.

Keywords

Arnicolide C; Hepatocellular carcinoma; MAPK; MYC; PI3K/Akt; Reactive oxygen species.

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