Revisiting Cell Death in Colorectal Cancer: The Rise of Ferroptosis as a Therapeutic Opportunity.

Abstract

Colorectal cancer (CRC) remains a global health concern and a leading cause of cancer mortality, where therapeutic resistance persists as the central barrier to sustained response. Most conventional therapies rely on apoptosis, but CRC frequently resists through p53 alterations, anti-apoptotic BCL-2 upregulation, and drug efflux mechanisms. Here, we explore unconventional cell death pathways, focusing on ferroptosis, as a strategy to overcome apoptosis-dependent therapeutic resistance in CRC. We discussed the molecular mechanisms of ferroptosis, including GPX4 blockade, iron dysregulation, and lipid metabolism remodeling, and emphasized their implications for drug-resistant CRC. Then, necroptosis, pyroptosis, and autophagy were discussed in relation to their crosstalk with ferroptosis. Preclinical models show that ferroptosis inducers (e.g., erastin, RSL3, talaroconvolutin) selectively kill chemoresistant CRC, including KRAS-mutant CRC, and potentiate the efficacy of conventional regimens. The therapeutic duality of autophagy, pyroptosis, and necroptosis in CRC is discussed, with emphasis on ferroptosis's ability to circumvent traditional mechanisms of resistance. Yet, clinical translation is hindered by insufficient pharmacokinetics, systemic toxicity, limited biomarker availability, tumor heterogeneity, compensatory antioxidant pathways, and the need for safer delivery platforms. We propose that ferroptosis is most likely to enter CRC therapy through rational combinations, biomarker-guided patient selection, and tumor-targeted delivery platforms rather than as a stand-alone cytotoxic strategy.