As an E3 ubiquitin ligase, Fbxo4 loss leads to the accumulation of Fxr1; while the ectopic expression of Fbxo4 reduces Fxr1 levels, resulting in the elevation of both p21Cip1 and p27Kip1 that can induce the senescence of HNSCC cells [1]. The gene discussed is FXR1; the disease is head and neck squamous cell carcinoma.