The implantation of esophageal stent loaded with iodine-125 (I-125) is one of the critical approaches for the treatment of advanced esophageal cancer, but one common complication after stent implantation is benign hyperplasia associated restenosis. The aim of the current study is to understand the role of glutathione peroxidase 2 (GPX2), a key member of the GPX family of antioxidant enzymes. Initially, we detected the increased levels of GPX2 and GPX1 in esophageal benign hyperplasia tissues. Further, we evaluated the effects of GPX2 in response to H2O2 induced apoptosis and LPS induced inflammation. We observed that GPX2 expression was also significantly increased in Het-1A. Silencing of GPX2 significantly increased H2O2-induced apoptosis and LPS-induced inflammation, but GPX2 overexpression did the opposite, suggesting a protective effect by GPX2. In addition, we identified that the protective effect of GPX2 is through the activation of autophagy, and PCBP2, a poly (rC) binding protein, binds to and stabilizes GPX2 mRNA. These findings reveal a role of GPX2 in esophageal hyperplasia, allowing for a better understanding of the underlying molecular mechanism, which could lead to identification of potential treatment for clinical benign restenosis following stent implantation with I-125.