Iron and liver fibrosis: Mechanistic and clinical aspects

Table 1 Iron-related characteristics and components of transforming growth factor-β pathway and bone morphogenetic protein signalling

Stimulant	Pathway	Type II receptors	Type I receptors	Receptor-SMADs phosphorylated	Common SMAD	Significance/feature of pathway
BMPs (Belong to TGF-β superfamily)	Canonical	BMPR2, ACVR2A, ACVR2B	ALK 1,2,3,6	SMAD-1/5/8	SMAD-4	Growth, differentiation, and developmental processes
	BMP-6 induced by iron-loading (Liver specific)[133]	BMPR2, ACVR2A	ALK-2/3	SMAD-1/5/8	SMAD-4	Iron-dependent hepcidin induction, modulated by HJV, HFE and TFR2[44]
TGF-β	Canonical	TGF-β-RII	ALK-5 (TGF-β-RI)	SMAD-2/3 (Stimulation is stable over time)[44]	SMAD-4	Growth, differentiation, developmental processes and fibrotic responses.
	Non-canonical TGF-β1 induced by iron-loading[29]	TGF-β-RII	ALK-5 (TGF-β-RI)	SMAD-1/5/8 (Transient stimulation, independent of cell type)[44]	SMAD-4	Hepcidin induction, independent of modulation by HJV, HFE and TFR2[44] and independent of BMP6-mediated activation of hepcidin
Activins (Belong to TGF-β superfamily)	Canonical[134]	ACVR2A, ACVR2B	ALK-4/7	SMAD-2/3	SMAD-4	Differentiation, proliferation and determine functions of several cell types
	Non-canonical Activin B induced by inflammation[134]	ACVR2A, ACVR2B	ALK-2/3 with HJV as co-receptor	SMAD-1/5/8	SMAD-4	Hepcidin induction during inflammation[135]

ACVR: Activin receptor; ALK: Activin receptor-like kinase; BMP: Bone morphogenetic protein; BMPR: Bone morphogenetic protein receptor; HFE: High iron protein; HJV: Hemojuvelin protein; SMAD: Small mothers against decapentaplegic protein; TFR: Transferrin receptor; TFR: Transferrin receptor; TGF-β: Transforming growth factor beta; TGF-β-R: Transforming growth factor beta receptor.