Epimedium-derived icarisid I induces oxidative stress and nephrotoxicity by suppressing PI3K/AKT/Nrf2/HO-1 signaling...

Epimedium, a traditional herbal medicine with a wide range of pharmacological uses, has been linked to adverse effects, including nephrotoxicity. Nevertheless, the specific toxic components and underlying mechanisms remain elusive. This research examined the nephrotoxic effects of icarisid I, a major flavonoid metabolite of Epimedium, and delved into its molecular mechanisms. The study demonstrated that icarisid I induces significant nephrotoxicity both in vitro and in vivo. In HK-2 cells, it triggered oxidative stress, indicated by altered SOD, GSH, and MDA levels, and induced apoptosis. In mice, it caused severe renal tubular damage and elevated plasma BUN and creatinine. Mechanistically, icarisid I potentially inhibited the PI3K/AKT pathway, leading to the suppression of Nrf2 and its downstream target HO-1. We conclude that icarisid I contributes to the nephrotoxicity by inducing oxidative stress and apoptosis via suppression of the PI3K/AKT/Nrf2/HO-1 pathway, a finding critical for the safety evaluation of Epimedium-derived compounds.