2. Academic Validation
  3. Penfluridol regulates p62 / Keap1 / Nrf2 signaling pathway to induce ferroptosis in osteosarcoma cells

Penfluridol regulates p62 / Keap1 / Nrf2 signaling pathway to induce ferroptosis in osteosarcoma cells

  • Biomed Pharmacother. 2024 Aug:177:117094. doi: 10.1016/j.biopha.2024.117094.
Xiangchen Zeng 1,  Guang-Xun Lin 1,  Xianhui Zeng 2,  Jiyuan Zheng 3,  Chong Ren 4,  Zhong Luo 4,  Keyi Xiao 1,  Naikun Sun 1,  Long Zhang 5,  Gang Rui 6,  Xiaohui Chen 7
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China.
  • 2 Department of Infectious Diseases, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou 570206, China.
  • 3 The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China.
  • 4 School of Medicine, Xiamen University, Xiamen 361102, China.
  • 5 Department of Pain, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China. Electronic address: kaenlong@163.com.
  • 6 Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China. Electronic address: reigang@163.com.
  • 7 Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China. Electronic address: chenxiaohui@xmu.edu.cn.
PMID: 38996707 DOI: 10.1016/j.biopha.2024.117094
Abstract

The cure rate for patients with osteosarcoma (OS) has stagnated over the past few decades. Penfluridol, a first-generation antipsychotic, has demonstrated to prevent lung and esophageal malignancies from proliferation and metastasis. However, the effect of penfluridol on OS and its underlying molecular mechanism remains unclear. This study revealed that penfluridol effectively inhibited cell proliferation and migration, and induced G2/M phase arrest in OS cells. In addition, penfluridol treatment was found to increased Reactive Oxygen Species (ROS) levels in OS cells. Combined with the RNA-Seq results, the anti-OS effect of penfluridol was hypothesized to be attributed to the induction of Ferroptosis. Western blot results showed that penfluridol promoted intracellular Fe2+ concentration, membrane lipid peroxidation, and decreased intracellular GSH level to induce Ferroptosis. Further studies showed that p62/Keap1/Nrf2 signaling pathway was implicated in penfluridol-induced Ferroptosis in OS cells. Overexpression of p62 effectively reversed penfluridol-induced Ferroptosis. In vivo, penfluridol effectively inhibited proliferation and prolonged survival in xenograft tumor model. Therefore, penfluridol is a promising drug targeting OS in the future.

Keywords

Ferroptosis; Osteosarcoma; P62/Keap1/Nrf2 signaling pathway; Penfluridol.

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