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

## TL;DR

This study reveals a new signaling pathway involving Sgk1, Stat3, Mycl, and Ctsk that regulates bone cell formation and suggests Sgk1 inhibition could treat osteoporosis.

## Contribution

The paper identifies a novel Sgk1-Stat3-Mycl-Ctsk signaling axis in osteoclastogenesis.

## Key findings

- Sgk1 regulates osteoclast differentiation by phosphorylating Stat3.
- Mycl, downstream of Stat3, directly regulates Ctsk transcription.
- Inhibiting Sgk1 increases bone mass and strength in vivo.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-025-24679-0.