Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and DNA damage, while inflammation driven by cytokine-regulated pathways accelerates tumourigenesis. We therefore conducted this narrative review to collate the available evidence on the link between iron homeostasis and inflammatory signalling in CRC and highlight potential diagnostic and therapeutic applications. Methods: This narrative review of preclinical and clinical studies explores the molecular and cellular pathways that connect iron regulation and inflammation to CRC. Key regulatory molecules, such as the transferrin receptor (TFRC), ferroportin (SLC40A1), ferritin (FTH/FTL), hepcidin, and IL-6, were reviewed. Additionally, we summarised the findings of transcriptomic, epigenomic, and proteomic studies. Relevant therapeutic approaches, including iron chelation, ferroptosis induction, and anti-inflammatory strategies, were also discussed. Results: Evidence suggests that CRC cells exhibit altered iron metabolism, marked by the upregulation of transferrin receptor (TFRC), downregulation of ferroportin, and dysregulated expression of ferritin. Inflammatory mediators such as IL-6 activate hepcidin and STAT3 signalling, which reinforce intracellular iron retention and oxidative stress. Increased immune evasion, epithelial proliferation, and genomic instability appear to be linked to the interaction between inflammation and iron metabolism. Other promising biomarkers include ferritin, hepcidin, and composite gene expression signatures; however, their clinical application remains limited. Although several preclinical studies support the use of targeted iron therapies and combination approaches with anti-inflammatory agents or immunotherapy, there is a lack of comprehensive clinical validation confirming their efficacy and safety in humans. Conclusion: Although preclinical studies suggest that iron metabolism and inflammatory signalling form an interconnected axis closely linked to CRC, translating this pathway into reliable clinical biomarkers and effective therapeutic strategies remains a significant challenge. Future biomarker-guided clinical trials are essential to determine the clinical relevance and to establish precision medicine strategies targeting the iron–inflammation crosstalk in CRC.
Ahmadi et al. (Wed,) studied this question.