Exploring Ferroptosis-Related Genes in Depression: Insights Into Molecular Mechanisms and Potential Therapies

Pengpeng Li,1,2 Yangyang Gao,3 Miaobo Li,4 Shiqing Du,2 Xudong Zhao,2 Yiting Zhou2 1Department of Neurosugery, Xi’an Aerospace Hospital of Northwest University, Xi’an, Shaanxi, 710000, People’s Republic of China; 2Department of Interventional Radiology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214125, People’s Republic of China; 3Department of Critical Care Medicine, Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 4Department of Critical Care Medicine, the Second Hospital of Lanzhou University, Lanzhou, Gansu, 730030, People’s Republic of ChinaCorrespondence: Xudong Zhao, Department of Interventional Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, 214125, People’s Republic of China, Email [email protected] Yiting Zhou, Email [email protected]: This study aimed to investigate the role of ferroptosis-related genes in depression pathogenesis and identify potential therapeutic strategies through integrated bioinformatics and traditional Chinese medicine (TCM) approaches.Methods: We analyzed the GSE38206 dataset comprising peripheral blood mononuclear cell samples from 9 MDD patients and 9 healthy controls. Bioinformatics analyses including differential expression screening, functional enrichment, and protein-protein interaction network construction were performed to identify ferroptosis-associated hub genes. Potential therapeutic agents were screened through connectivity mapping and TCM network pharmacology analysis.Results: Our analysis identified 60 ferroptosis-related differentially expressed genes and revealed 17 core genes that form a central regulatory network in depression. These genes are primarily involved in inflammatory response, iron metabolism, and oxidative stress pathways. We identified five potential small-molecule compounds (VX-702, gossypol, atomoxetine, TWS-119, and ibudilast) that may target these ferroptosis-related pathways. Additionally, network pharmacology analysis revealed several TCM compounds (including ginseng, saffron, and Salvia miltiorrhiza) that demonstrate multi-target regulatory capabilities consistent with TCM treatment principles.Conclusion: This study provides evidence supporting the involvement of ferroptosis-related mechanisms in depression and proposes a integrative treatment strategy combining targeted molecular interventions with TCM approaches. The findings offer new perspectives for developing therapeutic interventions, particularly for treatment-resistant depression.Keywords: depression, ferroptosis, bioinformatics, traditional chinese medicine, oxidative stress