Ubiquitination of ACSL4 by Parkin Suppresses Ferroptosis and Rescues Glucocorticoid-Induced Bone Loss.

Long-term glucocorticoids (GCs) use induces glucocorticoids-induced osteoporosis (GIOP), but the underlying mechanisms remain unclear. This study investigated the role of Parkin in regulating ACSL4-mediated ferroptosis in GIOP and developed a bone-targeted mRNA therapeutic strategy. Using dexamethasone (DEX)-treated bone marrow mesenchymal stem cells (BMSCs) and a GIOP mouse model, we found that GCs induced typical ferroptosis in BMSCs. Parkin expression was significantly downregulated in GIOP models. Parkin knockdown exacerbated DEX-induced lipid peroxidation, iron accumulation, and mitochondrial dysfunction, while inhibiting osteogenesis and promoting adipogenesis; Parkin overexpression reversed these phenotypes. Mechanistically, Parkin directly bound to ACSL4 and promoted its K48-linked polyubiquitination and proteasomal degradation. Based on these findings, we constructed DSS6-modified bone-targeted lipid nanoparticles (LNPs) (Parkin-LNP@DSS6), which efficiently encapsulated mRNA and exhibited excellent bone-homing ability. Parkin-LNP@DSS6 inhibited ferroptosis and restored osteogenic differentiation in vitro, and significantly improved bone microstructural parameters in GIOP mice. Transcriptome sequencing confirmed suppression of ferroptosis and fatty acid metabolism pathways. Collectively, this study reveals a novel mechanism by which Parkin inhibits BMSCs ferroptosis via K48 ubiquitination-mediated degradation of ACSL4 to alleviate GIOP, and provides a promising bone-targeted mRNA delivery strategy for GIOP and other ferroptosis-related bone diseases.