Fisetin suppresses ferroptosis through Nrf2 and attenuates intervertebral disc degeneration in rats

Chenchao Li; Yekai Zhang; Yuxin Deng; Yu Chen; Chenyu Wu; Xiaoying Zhao; Ximiao Chen; Xiangyang Wang; Yifei Zhou; Xiaolei Zhang; Naifeng Tian

doi:10.1016/j.ejphar.2023.176298

Fisetin suppresses ferroptosis through Nrf2 and attenuates intervertebral disc degeneration in rats

Eur J Pharmacol. 2024 Feb 5:964:176298. doi: 10.1016/j.ejphar.2023.176298. Epub 2023 Dec 23.

Authors

Affiliations

¹ Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325088, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325035, Zhejiang Province, China.
² Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325088, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325035, Zhejiang Province, China; Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, 310000, Zhejiang Province, China.
³ Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325088, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325035, Zhejiang Province, China; Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, 310000, Zhejiang Province, China. Electronic address: zhangxiaolei@wmu.edu.cn.
⁴ Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325088, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325035, Zhejiang Province, China; Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, 310000, Zhejiang Province, China. Electronic address: naifengtian@wmu.edu.cn.

PMID: 38145645
DOI: 10.1016/j.ejphar.2023.176298

Abstract

Low back pain, primarily caused by intervertebral disc degeneration (IVDD), lacks effective pharmacological treatments. Oxidative stress has been identified as a significant contributor to IVDD. This study aims to establish an in vitro model of IVDD induced by oxidative stress and identify potential therapeutic agents and their underlying mechanisms. By screening the natural product library, fisetin emerged as the most promising compound in suppressing cell death induced by oxidative stress in nucleus pulposus cells (NPCs). Furthermore, our investigation revealed that the cell death induced by oxidative stress was predominantly associated with ferroptosis, and fisetin demonstrated the ability to inhibit ferroptosis in NPCs. Mechanistic exploration suggested that the impact of fisetin on ferroptosis may be mediated through the Nrf2/HO-1 (Nuclear factor erythroid 2-related factor 2/heme oxygenase-1) axis. Notably, the in vivo study demonstrated that fisetin could alleviate IVDD in rats. These findings highlight fisetin as a potential therapeutic option for IVDD and implicate the involvement of the Nrf2/HO-1 pathway in its mechanism of action.

Keywords: Fisetin; IVDD; Nrf2; Oxidative stress.

MeSH terms

Animals
Ferroptosis* / drug effects
Flavonols* / pharmacology
Flavonols* / therapeutic use
Intervertebral Disc Degeneration* / drug therapy
NF-E2-Related Factor 2 / metabolism
Rats

Substances

fisetin
Flavonols
NF-E2-Related Factor 2