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

• Published in: Biomedicine & pharmacotherapy Vol. 177; p. 117094
• Main Authors: Zeng, Xiangchen, Lin, Guang-Xun, Zeng, Xianhui, Zheng, Jiyuan, Ren, Chong, Luo, Zhong, Xiao, Keyi, Sun, Naikun, Zhang, Long, Rui, Gang, Chen, Xiaohui
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.08.2024; Elsevier
• Subjects: Ferroptosis; Osteosarcoma; P62/Keap1/Nrf2 signaling pathway; Penfluridol; Ferroptosis; P62/Keap1/Nrf2 signaling pathway; Penfluridol; Osteosarcoma
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117094

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. •Penfluridol inhibited osteosarcoma cell proliferation in a method based on the dose.•p62 / Keap1 / Nrf2 signaling pathway as a potential mechanism of Penfluridol-mediated ferroptosis in osteosarcoma cells.•Penfluridol inhibited subcutaneous tumor proliferation and induced tumor cell ferroptosis without noticeable side effects.