CYBRD1, also known as duodenal cytochrome b (Dcytb), is a ferric reductase enzyme that was initially thought to be crucial for reducing dietary iron, enabling its uptake by the divalent metal ion transport system in the intestine [4,5,6]. It may be involved in pathways related to iron metabolism and has significance in maintaining iron homeostasis within the body.

However, studies using Cybrd1 -null mouse models found that the loss of Cybrd1 had little or no impact on body iron stores, even under iron-deficient conditions, suggesting that other mechanisms must exist for dietary iron reduction [4].

In the context of cancer, in colorectal cancer, DDX17 was shown to promote metastasis and epithelial-mesenchymal transition (EMT) via down-regulation of miR-149-3p, which led to increased CYBRD1 expression [1]. In ovarian cancer, high CYBRD1 expression was associated with poor prognosis, and it may affect disease progression through mechanisms such as increased iron uptake, immune microenvironment regulation, and involvement in ferroptosis and ERK signaling pathways [2]. In glioma, increased CYBRD1 expression was associated with aggravated clinical outcomes, and overexpression enhanced glioma cell aggressiveness and attenuated the response to IFN-α [3]. In lung adenocarcinoma, miR-423-3p could activate the FAK signaling pathway through targeting CYBRD1, promoting cell proliferation, invasion, adhesion, and EMT [7]. In gastric cancer, EGFR up-regulated a subset of miRNAs to inhibit CYBRD1, causing cisplatin (DDP) resistance [8].

In summary, Cybrd1, while not essential for dietary iron absorption as previously thought, plays significant roles in various disease processes, especially in cancer development and progression. Gene-knockout mouse models have been instrumental in revealing its non-essential role in iron absorption and its functions in cancer-related biological processes, providing valuable insights into potential therapeutic targets for these diseases.