Neuroprotective effects of icariin in animal models of depression and anxiety: a systematic review of preclinical studies

Icariin, a major bioactive flavonoid extracted from Epimedium species, has demonstrated promising neuroprotective and antidepressant-like effects in preclinical research. However, the magnitude and consistency of these effects remain unclear due to substantial methodological heterogeneity across studies. Therefore, we conducted a systematic review and meta-analysis to evaluate the antidepressant efficacy of icariin in rodent models of depression. Literature searches were performed in Scopus, PubMed and Embase up to May 2025, following PRISMA 2020 guidelines. Twenty-three studies were included in the qualitative synthesis, and thirteen provided sufficient data for quantitative analysis. icariin administration significantly improved anhedonia-like behavior in the sucrose preference test (SPT), with a pooled Hedges’ g of 2.26 (95% CI: 1.56–2.96), and markedly reduced immobility in the forced swim test (FST), with a pooled Hedges’ g of 3.64 (95% CI: 2.65–4.64), indicating strong and robust antidepressant-like effects. Both findings were comparable in magnitude to conventional antidepressants. Meta-regression revealed that longer duration of depression model induction was associated with stronger behavioral improvement, whereas dose did not significantly predict efficacy. Mechanistic evidence suggests that icariin acts through multi-target neuroprotective pathways, including enhancement of BDNF-mediated neuroplasticity, inhibition of neuroinflammation, and regulation of HPA-axis dysfunction. Although methodological variability, male-biased animal selection, and pharmacokinetic limitations were identified, the overall evidence supports icariin as a promising antidepressant candidate for further translational investigation.