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  3. Integrating network pharmacology and experimental validation to decipher the protective effect of icariin against testicular aging

Integrating network pharmacology and experimental validation to decipher the protective effect of icariin against testicular aging

  • Ecotoxicol Environ Saf. 2025 Sep 15:303:119063. doi: 10.1016/j.ecoenv.2025.119063.
Jiandong Sun 1,  Chengyu Lv 2,  Zihang Lin 3,  Shanshan Luo 3,  Shumin Liao 3,  Xiuli Lian 4,  Yue Liu 4,  Lvjing Luo 3,  Mei Zheng 3,  Dini Zhang 3,  Xuanyi Wang 3,  Shie Wang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Department of Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China; Department of Andrology, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350122, PR China; Department of Reproductive Medicine Centre, First Affiliated Hospital of Fujian Medical University, Fuzhou 350122, PR China.
  • 2 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou350001PR China.
  • 3 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China.
  • 4 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Department of Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China.
  • 5 Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou 350122, PR China; Department of Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China. Electronic address: shiewang@fjmu.edu.cn.
PMID: 40961599 DOI: 10.1016/j.ecoenv.2025.119063
Abstract

During male reproductive aging, levels of Reactive Oxygen Species (ROS) increase progressively in the testes. Excessive ROS directly reduce testosterone synthesis and impair spermatogenesis in the testes, inducing male reproductive senescence. As a bioactive monomer derived from traditional Chinese medicine, icariin (ICA) exerts protective effects against ROS after exposure to environmental toxicants, including di(2-ethylhexyl) phthalate (DEHP). In the present study, we aimed to explore the therapeutic effects of ICA on male reproductive senescence. In particular, we examined the protective effects of icariin in aged murine models through oral gavage and elucidated its molecular mechanisms via integrated network pharmacology, molecular docking, and molecular dynamics simulation approaches. We identified 125 potential targets of icariin in testicular aging. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these targets are associated with ROS scavenging, lipid storage regulation, androgen metabolism, and Ferroptosis as well as cellular senescence and PI3K/Akt signaling pathways. The top five hub targets (ESR1, TP53, BCL2, HIF1A, and TNF) demonstrated high binding potential with icariin, as supported by molecular docking and molecular dynamics simulations. Furthermore, in vivo experiments showed that icariin treatment reduces ROS, malondialdehyde, and Fe2 + levels significantly in aging testes. Icariin activated the ESR1/Akt pathway, thereby restoring testosterone synthesis and mitigating cellular senescence in 12-month-old mice. These findings demonstrate the critical role of icariin in ameliorating testicular aging and provide a foundation for detailed analyses of its molecular mechanisms.

Keywords

Icariin; Molecular docking; Molecular dynamics simulation; Network pharmacology; Testicular aging.

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