1. Academic Validation
  2. Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

  • Cell Death Discov. 2023 Aug 14;9(1):296. doi: 10.1038/s41420-023-01597-6.
Kunpeng Tian # 1 2 Jinrui Wei # 3 Ru Wang # 1 Mingming Wei # 4 Fei Hou 4 Lichuan Wu 5
Affiliations

Affiliations

  • 1 School of Medicine, Guangxi University, Nanning, 530004, Guangxi, PR China.
  • 2 Pediatrics Research Institute of Hunan Province, Hunan Children's Hospital, Changsha, 410007, Hunan, PR China.
  • 3 Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, PR China.
  • 4 The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • 5 School of Medicine, Guangxi University, Nanning, 530004, Guangxi, PR China. richard_wu@gxu.edu.cn.
  • # Contributed equally.
Abstract

Liver Cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver Cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including Apoptosis, necrosis, and Autophagy. Targeting Ferroptosis is recognized as a promising potential therapeutic modality for liver Cancer. Activating transcription factor 3 (ATF3) is an important Ferroptosis inducer and targeting ATF3 offers a potential means to Cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver Cancer effects in vitro and in vivo. Compound 6j could induce liver Cancer cells Ferroptosis by promoting the accumulation of intracellular Fe2+, Reactive Oxygen Species (ROS), and MDA. Inhibition of Ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced Ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of Ferroptosis inducers and the development of anti-liver Cancer drugs.

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