A novel Keap1 inhibitor iKeap1 activates Nrf2 signaling and ameliorates hydrogen peroxide-induced oxidative injury and apoptosis in osteoblasts

被引：33

作者：

Zheng, Yue-huan ^{[1
]}

Yang, Jian-jun ^{[2
]}

Tang, Pei-jun ^{[3
]}

Zhu, Yuan ^{[1
]}

Chen, Zhe ^{[1
]}

She, Chang ^{[4
]}

Chen, Gang ^{[1
]}

Cao, Peng ^{[1
]}

Xu, Xiang-yang ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Orthoped, Sch Med, Shanghai, Peoples R China

[2] Tongji Univ, Peoples Hosp 10, Dept Orthoped, Shanghai, Peoples R China

[3] Soochow Univ, Peoples Hosp Suzhou 5, Affiliated Infect Dis Hosp, Dept Pulm, Suzhou, Peoples R China

[4] Soochow Univ, Affiliated Hosp 2, Dept Orthoped, Suzhou, Peoples R China

来源：

CELL DEATH & DISEASE | 2021年 / 12卷 / 07期

基金：

美国国家科学基金会;

关键词：

PIGMENT EPITHELIUM-CELLS; RETINAL GANGLION-CELLS; PROTECTS OSTEOBLASTS; NRF2/HO-1; NICOTINE; STRESS; EXPRESSION; ITACONATE; PROMOTES; PATHWAY;

D O I：

10.1038/s41419-021-03962-8

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling. We here tested its potential effect against hydrogen peroxide (H2O2)-induced oxidative injury in osteoblasts. In primary murine and human osteoblasts, iKeap1 robustly activated Nrf2 signaling at micromole concentrations. iKeap1 disrupted Keap1-Nrf2 association, causing Nrf2 protein stabilization, cytosol accumulation and nuclear translocation in murine and human osteoblasts. The anti-oxidant response elements (ARE) activity and transcription of Nrf2-ARE-dependent genes (including HO1, NQO1 and GCLC) were increased as well. Significantly, iKeap1 pretreatment largely ameliorated H2O2-induced reactive oxygen species production, lipid peroxidation and DNA damage as well as cell apoptosis and programmed necrosis in osteoblasts. Moreover, dexamethasone- and nicotine-induced oxidative injury and apoptosis were alleviated by iKeap1. Importantly, Nrf2 shRNA or CRISPR/Cas9-induced Nrf2 knockout completely abolished iKeap1-induced osteoblast cytoprotection against H2O2. Conversely, CRISPR/Cas9-induced Keap1 knockout induced Nrf2 cascade activation and mimicked iKeap1-induced cytoprotective actions in murine osteoblasts. iKeap1 was ineffective against H2O2 in the Keap1-knockout murine osteoblasts. Collectively, iKeap1 activated Nrf2 signaling cascade to inhibit H2O2-induced oxidative injury and death of osteoblasts.

引用

页数：10

共 54 条

[31]

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1 [J].