SCD1 Regulates Osteoclast Differentiation by Modulating Arachidonic Acid Metabolism and Mitochondrial Homeostasis

Bone homeostasis is maintained by a dynamic balance between bone formation and resorption. Here, we link lipid metabolism to osteoclast differentiation by identifying stearoyl-CoA desaturase-1 (SCD1) as a key regulatory factor. Notably, SCD1 expression was significantly upregulated during osteoclast differentiation, and knockdown of SCD1 or inhibiting its activity with A939572 significantly impaired osteoclast formation. Integrating RNA sequencing and metabolomics, we revealed that SCD1 inhibition altered arachidonic acid metabolism and influenced mitochondrial homeostasis. Mechanistically, A939572 upregulated COX1 and HPGDS expression, leading to the accumulation of Prostaglandin D2 (PGD2), which in turn suppressed osteoclast differentiation. Finally, we engineered a biomimetic nanovesicle (POCM-NP@A939572) coated with preosteoclast membrane for targeted delivery. In vivo, POCM-NP@A939572 exhibited superior efficacy in preventing bone loss compared to A939572 alone. Collectively, this study demonstrates the SCD1-COX1-PGD2 axis as a therapeutic target and demonstrates the value of targeted nanomedicine in managing bone diseases.