Maintenance of iron homeostasis is crucial for human health.Failure to keep iron balance could lead to multiple diseases.To explore the mechanistic network of iron regulators in maintaining iron homeostasis and staying healthy, we initiated systematic investigations utilizing knockout mouse models, epidemiology, and meta-analysis.Recently significant findings are listed as followings: 1) Functionally characterized Fpnl as a major iron exporter in macrophage and hepatocytes, and further defined hepatocyte Fpnl as one of the important players in iron mobilization, iron storage, and intestinal iron absorption to maintain systemic iron homeostasis (Blood, 2011);2) We observed metalloreductase Steap3 coordinates with Fpnl to regulate systemic iron homeostasis and inflammatory responses (Haematologica, 2012);3) Defined significant association between TMPRSS6 polymorphisms and decreased iron status, and refmed genetic risk factors for iron deficiency and iron-deficiency anemia;4) Discovered TMPRSS6 variants, which mediated by plasma ferritin, were significantly associated with lower risk of type 2 diabetes in Chinese Hans (Am J Clin Nutr.2012);5) Our meta-analysis provided rigorous statistical evidences for supporting iron homeostasis was changed and might have causal roles in the development of Alzheimers disease (AD), cardiovascular diseases and metabolic syndrome;and 6) We screened and measured the level of hepcidin expression in cultured cells treated with medicinal plant and food extracts.The data indicated that Jixueteng and bleak bean could serve as potent novel hepcidin inhibitors, which may be further modified and optimized to become an effective food supplement or adjuvant treatment options for diseases in which hepcidin is overexpressed, such as ACD or IRIDA (Journal of Nutrition.2013).Taken together, we believe our serial studies set up a foundation to further translate the findings to therapeutic target stratification in iron metabolism related diseases, including many chronic diseases.