Our study uncovered a novel mechanism in which RYR2 competitively interacted with the E3 ubiquitin ligase and MDM2 and protected p53 from MDM2-mediated degradation; however, RYR2 was frequently downregulated in ESCC tumor tissues, which led to decreased protein levels of p53 and p21, promoting malignancy in ESCC. The gene discussed is RYR2; the disease is esophageal squamous cell carcinoma.