These protective effects of fisetin were further validated in vivo in a rat model of puncture-induced IDD, in which fisetin administration restored loss of disc height and intensity, ameliorated tissue structure by inhibiting ECM degradation, limited lipid peroxidation and senescence by reducing glutathione peroxidase (GPX) 4 and p16INK4a expression, respectively and increased expression levels of the Nrf2/HO-1 axis [43]. The gene discussed is CDKN2A; the disease is intervertebral disk degenerative disorder.