Almost all the OIS inducers trigger the activation of p53, induce the expression of its transcriptional target p21, and increase the expression of p16.[48] p21 and p16 are downstream of pERK1/2 and are tumor suppressors that induce cellular senescence and cell cycle arrest.[49, 50, 51] Studies have shown that inhibiting pERK1/2 or pAKT can activate p16 and p21, promoting cell senescence.[52, 53, 54] Our research has uniquely demonstrated that inhibiting pERK1/2, which is upregulated by PBRM1 knockdown, can activate p53, p16, and p21, thereby inducing cell senescence in iCCA. The gene discussed is PBRM1; the disease is neoplasm.