Ferroptosis as a Novel Therapeutic Strategy to Overcome Multidrug Resistance in Colorectal Cancer

Colon cancer (CC) remains a leading cause of cancer-related mortality worldwide, with multidrug resistance (MDR) presenting a formidable barrier to successful chemotherapy. Ferroptosis—an iron-dependent, lipid peroxidation-driven form of cell death—offers a novel therapeutic avenue to bypass MDR by exploiting metabolic vulnerabilities distinct from traditional apoptosis pathways. Emerging evidence reveals a dynamic interplay between MDR and ferroptosis: MDR cancer cells suppress ferroptosis through NRF2/GPX4-mediated antioxidant upregulation, iron sequestration by ferritin, and lipid metabolism reprogramming, including SREBP1-driven monounsaturated fatty acid accumulation, while ABC transporters actively efflux ferroptosis inducers. On the other hand, ferroptosis inducers such as erastin and RSL3 have the potential to overcome apoptotic resistance and avoid efflux pathways, which recover therapeutic efficacy. This review first describes the primary mechanisms of chemotherapy resistance in colon cancer and then explains the molecular processes that prevent ferroptosis in resistant cells. We also review recent data on the complex interactions between resistance to chemotherapy and ferroptosis, and outline approaches that may stimulate iron accumulation to reverse MDR. By emphasizing novel methods to induce ferroptosis, this review highlights that this approach is a promising strategy to overcome chemotherapy resistance in colon cancer and will facilitate the development of more precise and efficient treatment.