Nrf2: A critical participant in regulation of apoptosis, ferroptosis, and autophagy in gastric cancer

Abstract

Nuclear factor erythroid 2-related factor-2 (Nrf2) is a specific transcription factor that maintains redox homeostasis by regulating the expression of anti-oxidative stress-related genes. Hyperactivation of Nrf2 is involved in tumor progression and is associated with chemoresistance in a large number of solid tumors. Programmatic cell death (PCD), such as apoptosis, ferroptosis, and autophagy, plays a crucial role in tumor development and chemotherapy sensitivity. Accumulating evidence suggests that some anti-tumor compounds and genes can induce massive production of reactive oxygen species (ROS) via inhibiting Nrf2 expression, which exacerbates oxidative stress and promotes Gastric cancer (GC) cell death, thereby enhancing the sensitivity of GC cells to chemotherapy-induced PCD. In this review, we summarize the role of antitumor drugs in interfering in three different types of PCD (apoptosis, ferroptosis, and autophagy) in GC cells by modulating Nrf2 expression, as well as the molecular mechanisms through which targeting Nrf2 brings about PCD and chemosensitivity. It is reasonable to believe that Nrf2 serves as a potential therapeutic target, and targeting Nrf2 by drug or gene regulation could provide a new strategy for the treatment of GC.