Iron-Dependent KDM4D Activity Controls the Quiescence-Activity Balance of MSCs via the PI3K-Akt-Foxo1 Pathway [CUT&Tag]

Iron deficiency is a common nutritional deficit that can lead to organ damage or dysfunction. Research is increasingly linking iron deficiency to dysfunction of bone metabolism, although the exact mechanisms remain unclear. Some studies suggest that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. Whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity is unclear. In our study, we discovered that KDM4D plays a pivotal role in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This change led to increased heterochromatin with H3K9me3 near the PIK3R3 promoter, hindering the expression of PIK3R3. Subsequently, the activation of quiescent MSCs was inhibited via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice exhibited significantly inhibited bone marrow MSC activation and reduced bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.