Redox-regulated cell death in gastric cancer: Molecular insights and therapeutic opportunities.

Abstract

Oxidative stress, resulting from the disruption of redox homeostasis, is increasingly recognized as a central driver of gastric cancer pathogenesis and a critical determinant of cell fate. An imbalance between reactive oxygen species (ROS) production and cellular antioxidant defenses leads to oxidative stress, which may ultimately result in cellular oxidative death. Helicobacter pylori (H. pylori), through its virulence factors, induces a vicious cycle of oxidative stress and inflammation that collectively remodels the tumor microenvironment. Gastric cancer is molecularly heterogeneous, and ROS demonstrate profound context dependency across these different subtypes, with distinct mechanisms governing ROS generation, antioxidant defense, and redox-regulated cell death. Importantly, ROS orchestrate a diverse repertoire of cell death modalities in gastric cancer, including ferroptosis, apoptosis, necroptosis, cuproptosis, paraptosis, pyroptosis, and oxeiptosis via a regulatory network involving key molecules such as GPX4, SLC7A11, NRF2, and caspases. In-depth research into the mechanisms of cell death holds promise for developing preventive and therapeutic agents. This review summarizes the mechanisms of ROS‑regulated cell death and explores various therapeutic strategies, including the combined use of small‑molecule compounds and emerging nanomaterial‑based approaches, alongside conventional chemotherapy, immunotherapy, and radiotherapy, to target oxidative stress. It also highlights recent advances, opportunities, and challenges in translating these strategies into gastric cancer therapy. In conclusion, this review offers a mechanistically grounded framework for developing redox-targeted precision therapies in gastric cancer.

Key Findings

• Oxidative stress from disrupted redox homeostasis is a central driver of gastric cancer pathogenesis and influences cell fate.
• ROS regulate diverse cell death modalities in gastric cancer, including ferroptosis, apoptosis, necroptosis, cuproptosis, paraptosis, pyroptosis, and oxeiptosis through molecules such as GPX4, SLC7A11, NRF2, and caspases.
• Therapeutic strategies targeting oxidative stress, including small molecules, nanomaterials, chemotherapy, immunotherapy, and radiotherapy, show promise for precision treatment of gastric cancer.

Clinical Significance

Citation

Qi He, Cao Chenbin, Li Wenyanet al.. Redox-regulated cell death in gastric cancer: Molecular insights and therapeutic opportunities. Journal of physiology and biochemistry. 2026-Jul-25.