Icariin Modulates the Reproductive-Immune Axis: Molecular Insights and Therapeutic Potential

The immune system is a pivotal regulator of reproductive physiology, maintaining tissue homeostasis essential for successful pregnancy while contributing to infertility and reproductive disorders when dysregulated. Natural products represent a valuable source of novel immunomodulatory agents. Icariin (ICA), a prenylated flavonoid glycoside isolated from Epimedium species (Horny Goat Weed), has a long-standing traditional use for "invigorating yang," which modern research attributes to its reproductive function-enhancing properties. This review synthesizes emerging evidence that the beneficial effects of ICA on female and male reproductive health are primarily mediated through its sophisticated immunomodulatory actions on the reproductive-immune axis. We systematically dissect the molecular mechanisms by which ICA reprograms the reproductive immune microenvironment, focusing on its regulation of macrophage polarization, T-helper cell (Th1/Th2/Th17) and regulatory T-cell (Treg) balance, and suppression of key pro-inflammatory signaling pathways (NF-κB, NLRP3 inflammasome, JAK-STAT) in ovarian, uterine, and testicular tissues. This review provides a detailed account of how ICA modulates reproductive disorders via regulating immune responses, with the aim of offering innovative strategies for the design of novel immunomodulatory therapies targeting reproductive diseases.