METTL9 mediated N1-Histidine methylation of SLC39A7 confers ferroptosis resistance and inhibits adipogenic differentiation in mesenchymal stem cells.

Abstract

Osteoporosis is a prevalent systemic metabolic disease, and an imbalance in the adipogenic and osteogenic differentiation of mesenchymal stem cells (MSCs) plays a crucial role in its pathogenesis. Thus, elucidating the mechanisms that regulate MSC lineage allocation is urgently needed. METTL9 was recently characterized as a novel N1-histidine methyltransferase that performs a wide range of functions. however, the role of METTL9 in the imbalance of MSC differentiation in osteoporosis remains unclear. In this study, we found that METTL9 expression was downregulated in osteoporosis, and further adipogenic functional experiments revealed that METTL9 negatively regulated the adipogenic differentiation of MSCs both in vitro and in vivo. Mechanistically, METTL9 mediated methylation of SLC39A7 at the His45 and His49 residues suppressed ferroptosis through the endoplasmic reticulum (ER) stress regulatory protein kinase R-like endoplasmic reticulum kinase (PERK)/ATF4 signaling pathway and the downstream protein SLC7A11. Moreover, SLC7A11 transported cystine for intracellular glutathione synthesis, eliminating intracellular reactive oxygen species (ROS) and inhibiting MSC adipogenic differentiation. Additionally, METTL9 overexpression significantly alleviated bone loss in ovariectomy (OVX) model mice. In summary, our results suggest that the METTL9/SLC39A7 axis may be a promising diagnostic and therapeutic target for osteoporosis.