NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury

作者：Zhuan Feng, Yifei Qin, Fei Huo, Zhe Jian, Xiaomin Li, Jiejie Geng, Yong Li, Jiao Wu · 发表于：Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · 年份：2021 · DOI：10.1016/j.bbadis.2021.166287 · 被引用次数：121 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、Cancer, Lipids, and Metabolism

Oxidative stress and lipid peroxidation are major causes of skin injury induced by ultraviolet (UV) irradiation. Ferroptosis is a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids and contributes to kinds of tissue injuries. However, it remains unclear whether the accumulation of lipid peroxides in UV irradiation-induced skin injury could lead to ferroptosis. We generated UV irradiation-induced skin injury mice model to examine the accumulation of the lipid peroxides and iron. Lipid peroxides 4-HNE, the oxidative enzyme COX2, the oxidative DNA damage biomarker 8-OHdG, and the iron level were increased in UV irradiation-induced skin. The accumulation of iron and lipid peroxidation was also observed in UVB-irradiated epidermal keratinocytes without actual ongoing ferroptotic cell death. Ferroptosis was triggered in UV-irradiated keratinocytes stimulated with ferric ammonium citrate (FAC) to mimic the iron overload. Although GPX4 protected UVB-injured keratinocytes against ferroptotic cell death resulted from dysregulation of iron metabolism and the subsequent increase of lipid ROS, keratinocytes enduring constant UVB treatment were markedly sensitized to ferroptosis. Nicotinamide mononucleotide (NMN) which is a direct and potent NAD+ precursor supplement, rescued the imbalanced NAD+/NADH ratio, recruited the production of GSH and promoted resistance to lipid peroxidation in a GPX4-dependent manner. Taken together, our data suggest that NMN recrui...