皮肤细胞衰老（cellular senescence，CS）是皮肤早衰和皮肤癌等发生发展主要原因，然而其调控机制和干预策略尚未清楚。我们的前期实验结果显示谷胱甘肽过氧化物酶4（GPX4）可能作为调控皮肤CS的重要靶点，并发现药食同源中药生姜中的姜酚类化合物具有激活GPX4的活性。本项目拟以生姜中的8-姜酚作为探针，采用氧化脂质组学等先进技术，深入研究GPX4缺失所介导的磷脂过氧化在调控皮肤CS的作用，研究药食同源中药活性成分抗皮肤CS的作用及机制。该机制重点从研究活性成分激活GPX4抑制磷脂过氧化的产生，下调PML表达，抑制PML NBs的形成，进而抑制CS信号通路激活的角度来进行。并在此基础上，利用mechanism-based design策略从药食同源中药中筛选出激活GPX4抗皮肤CS的活性成分。本项目将揭示药食同源中药抗皮肤CS的科学内涵，为抗皮肤早衰创新药物的开发提供科学依据。

Skin cellular senescence (CS) is a major cause of the occurrence and development of skin premature aging and skin cancer, however, its regulatory mechanism and intervention strategy remain unclear. Our previous experiment results showed that Glutathione peroxidase 4 (GPX4) may serve as an important target for regulating skin CS, and it was found that gingerol compounds in Rhizoma Zingiberis Recens, a homology of medicine and food, were potential to activate GPX4. Therefore, this project intends to take 8-gingerol as probe and use oxidative lipidomics along with other advanced technologies to further explore the role of phospholipid peroxidation mediated by the GPX4 deletion in the regulation of skin CS and to study the anti-skin CS effect and mechanism of homology of medicine and food. The mechanism involved that these active compounds against skin CS by inhibiting specific phospholipid peroxidation by activating GPX4, then down-regulating the expression of PML, inhibiting the formation of PML NBs in the nucleus, and further inhibiting the activation of the CS signaling pathway. On this basis, mechanism-based design strategy was performed to screen the active compounds which could activate GPX4 and inhibit phospholipid peroxidation against skin CS from homology of medicine and food. This project may contribute to reveal the mechanism and scientific connotation of the anti-skin CS effect of homology of medicine and food and provide scientific basis for the development of innovative anti-skin premature aging drugs.