Mycl, activated by Sgk1-phosphorylated Stat3, mediates osteoclastogenesis via Ctsk transcriptional regulation.

Osteoclast differentiation is essential for bone homeostasis, yet its molecular regulation remains incompletely understood. Here, we identify serum/glucocorticoid-regulated kinase 1 (Sgk1), an AGC kinase responsive to hormonal signals, as a key regulator of osteoclastogenesis. Mechanistically, inhibition of Sgk1 reduces Stat3 phosphorylation at Tyr705, leading to the downregulation of Mycl, a less characterized member of the MYC family of transcription factors. We demonstrate that Mycl directly binds to the Ctsk promoter, and functional assays confirm its critical role; Mycl overexpression rescued the osteoclast differentiation impairment caused by Sgk1 inhibition. In vivo, treatment with the Sgk1 inhibitor GSK650394 increased trabecular bone mass and enhanced mechanical strength without compromising osteoblast activity. Collectively, our findings define a novel Sgk1-Stat3-Mycl-Ctsk signaling axis that contributes to osteoclastogenesis and suggest that Sgk1 inhibition represent a potential therapeutic strategy for osteoporosis.