In a recent study, Cordycepin was identified to activate AMPK via interaction with the γ1 subunit only in lipid regulation of HepG2 cancer cells55, here, in our study, we further identified cordycepin can activate AMPK through the interaction with both the α1 and γ1 subunit of AMPK near the autoinhibitory domain which directly relieve autoinhibition, then to promote autophagic degradation of Keap1, and this mechanism is demonstrated to play an important role in the prevention of cell senescence and mitigation of radiation ulcer. This evidence concerns the gene KEAP1 and cancer.