Hepcidin modulation in human diseases: From research to clinic

Table 1 Positive and negative regulators of hepcidin production, signalling pathways involved and human diseases either caused by defective function of the regulatory protein (Hemochromatosis, IRIDA) or inducing activation or suppression of the regulatory pathway

Positive regulators	Signalling pathway	Human disease	Negative regulators	Signalling pathway	Human disease
Inflammation [IL-6, IL-1α]	STAT-3	Anemia of chronic disease	Hypoxia [HIF1, sHJV, ROS]	HIF-1, BMPs/SMAD Oxygenases inhibition	--
Iron stores [mHJV]	BMPs/ SMAD4	Hemochromatosis	Iron stores [Matriptase2, s-HJV, GDF15]	BMPs/SMAD inhibition	IRIDA, iron deficiency
Iron stores [HFE, TfR2]	BMPs/ SMAD4	Hemochromatosis	Erythropoiesis [GDF15, others?]	BMPs/SMAD inhibition others?	Thalassemia, CDA1
Liver metabolic activities	C/EBPα		Erythropoietin?	C/EBPα block
Oxygenases	?		Oxidative stress [ROS]	C/EBPα, STAT3 block; Oxygenases inhibition HDAC activation	Hepatitis C viral and alcoholic liver disease

IRIDA: Iron refractory iron deficiency anemia; CDA1: Congenital dyserythropoietic anemia type 1; Oxygenases: Family of 2-oxoglutarate-dependent oxygenases including prolyl and aspariginyl hydroxilases, PHDs and FIH. References: Andrews[6], De Domenico et al[7], Braliou et al[42], Choi et al[43], Nemeth[38] , Pinto et al[39], Pak et al[40], Tanno et al[41], Lakhal et al[54], Tamary et al[55], Silvestri et al[57], Silvestri et al[59], Miura et al[101], Harrison-Findik[46].