Ndrg3, an N-myc downstream regulated gene, has been implicated in multiple biological processes and diseases. It may play roles in hypoxia-related signaling, as oxygen negatively regulates its protein-level expression via the PHD2/VHL system, and lactate can stabilize it, activating the Raf-ERK pathway to promote angiogenesis and cell growth under hypoxia [3].

In cancer, Ndrg3 shows diverse effects. In papillary thyroid carcinoma, serum Ndrg3 is an independent protective factor, and its decrease can be used for differential diagnosis between benign thyroid nodules and papillary thyroid carcinoma [1]. In contrast, in chronic myelogenous leukemia, Ndrg3 is highly expressed and promotes cell proliferation and imatinib resistance by promoting β-catenin accumulation in the nucleus [2]. In hepatocellular carcinoma, high Ndrg3 expression facilitates metastasis by promoting nuclear translocation of β-catenin [4]. In colorectal cancer, it facilitates metastasis through activating Src phosphorylation [6]. Also, high Ndrg3 expression is associated with poor prognosis in gastric cancer [7], and in invasive breast cancer, it is linked to an aggressive phenotype and poor outcome [8]. In gastric cancer, the SNHG20/miR-140-5p/Ndrg3 axis may be involved in 5-fluorouracil resistance [9], and in osteosarcoma, the LINC01410/miR-122-5p/Ndrg3 axis is involved in cell proliferation and migration [10]. In osteoarthritis patients, Ndrg3 expression is high, suggesting its possible relation to the disease's development [5].

In conclusion, Ndrg3 is involved in various biological processes such as hypoxia-related signaling and is significantly associated with multiple diseases, especially different types of cancers. Understanding the role of Ndrg3 through functional studies, although lacking gene-knockout or conditional-knockout mouse model-based evidence in the provided references, may provide insights into disease mechanisms and potential therapeutic targets for cancer and osteoarthritis.