Integrative genomic profiling of iron homeostasis predicts clinical outcomes and identifies HAMP/hepcidin as a therapeutic target in colorectal cancer

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, often diagnosed at advanced stages. Iron homeostasis, a crucial metabolic pathway in cancer, significantly impacts tumor progression. This study systematically investigated the function and significance of iron homeostasis-related genes (IHGs) in CRC, leading to the establishment of iron homeostasis-related molecular subtypes (IHMS) and a prognostic model based on their expression profiles of IHGs. Both IHMS and the model showed strong predictive accuracy for prognosis, clinical parameters, and response to immunotherapy. Patients classified as IHMS-B or exhibiting high model risk scores had poorer prognoses, while those categorized as IHMS-C or with low model risk scores were associated with more favorable outcomes and increased sensitivity to immunotherapy across multiple datasets. The model key gene HAMP (encoding hepcidin) was identified as a key oncogenic regulator that promotes CRC progression; elevated levels of HAMP/hepcidin were linked to peritoneal metastasis. Knocking out HAMP resulted in reduced tumor burden and inhibited proliferation and cancer stemness in both in vivo and in vitro models. Additionally, integration of in-house bulk-seq and tissue-array data further substantiated the clinical significance of HAMP/hepcidin and its association with immune landscapes. In conclusion, both IHMS and the model serve as effective predictors for CRC prognosis and patient stratification. HAMP/hepcidin, a central regulator of iron homeostasis, plays a pivotal role in driving the progression and metastasis of CRC, underscoring the therapeutic potential of targeting the HAMP-mediated iron axis to improve clinical outcomes in CRC.