Research progress on ferroptosis in drug resistance and therapy of gastric cancer

The clinical management of gastric cancer (GC) is frequently challenged by the development of drug resistance, leading to poor patient outcomes. This review aims to explore the role of ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, in overcoming this therapeutic hurdle. Our objective is to provide a theoretical foundation for developing novel strategies to reverse drug resistance in GC by targeting the ferroptosis pathway.

This review systematically elucidates the core regulatory mechanisms of ferroptosis and analyzes its key role in mediating drug resistance in GC. We synthesize current literature to explore potential therapeutic strategies that leverage ferroptosis induction to sensitize cancer cells. Furthermore, we critically examine the complex interplay between ferroptosis and the tumor microenvironment (TME) and discuss the challenges associated with translating these findings into personalized treatment approaches, integrating insights from emerging technologies.

Our analysis confirms that ferroptosis is governed by a precise regulatory network involving glutathione metabolism, lipid peroxidation, and iron homeostasis, which is frequently dysregulated in GC. We identify that key mechanisms of conventional drug resistance are linked to the evasion of ferroptosis. Consequently, several potential therapeutic strategies, including the use of ferroptosis inducers (FINs) and combination therapies, show promise in resensitizing resistant GC cells. The review also highlights the dual role of the TME, which can either suppress or promote ferroptosis, adding a layer of complexity. Finally, we identify significant challenges in patient stratification and the need for reliable biomarkers to achieve personalized ferroptosis-based therapies.

Targeting ferroptosis presents a promising and innovative research avenue for reversing drug resistance in gastric cancer. Strategies designed to induce ferroptosis effectively overcome common resistance mechanisms and hold significant therapeutic potential. Future research must focus on integrating multi-omics technologies and advanced drug delivery systems to decipher the complex regulatory networks of ferroptosis within the TME and to develop biomarkers for personalized treatment, thereby paving the way for improved clinical outcomes.