IRP1 deficiency promotes fibroblast activation through iron dysregulation: protective modulation by H₂S

Abstract

Iron is essential for various body functions, and intracellular iron metabolism is a precisely regulated process. Iron regulatory protein 1 (IRP1) acts as a key regulator of cellular iron metabolism. IRP1 dysfunction has been linked to oxidative stress, metabolic imbalances, and fibrosis. Hydrogen sulfide (H2S), an important gasotransmitter with antioxidant and cytoprotective properties, has emerged as a key player in both health and diseases. The regulatory roles of H2S on IRP1-related iron metabolism and fibroblast cell activation have not been explored. This study investigated the interaction of H2S and IRP1 on iron metabolism and cell fibrosis by using cultured mouse embryonic fibroblasts (MEFs). Here it was found that IRP1 deficiency increased labile iron level, promoted cell adhesion and proliferation, induced oxidative stress, stimulated the expressions of cell fibrosis-related genes in MEFs. Iron overload also strengthened cell proliferation and oxidative stress. In contrast, exogenously applied NaHS would be able to reverse IRP1 deficiency and iron overload-caused cell dysfunctions. It was further found that IRP1 deficiency or iron overload induced H2S generation but had no effect on the protein levels of H2S-generating enzymes in MEFs. Taken together, this study suggests that H2S would protect from IRP1 deficiency-induced iron overload and cell fibrosis. This study may pave the way for targeted therapeutic strategies in iron dysregulation disorders and fibrosis- related diseases.