GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux

Glutathione S-transferase P1(GSTP1) is known for its transferase and detoxification activity. Based on diseasephenotype genetic associations, we found that GSTP1 might be associated with bone mineral density through Mendelian randomization analysis. Therefore, this study was performed both in vitro cellular and in vivo mouse model to determine how GSTP1 affects bone homeostasis. In our research, GSTP1 was revealed to upregulate the S-glutathionylation level of Pik3r1 through Cys498 and Cys670, thereby decreasing its phosphorylation, further controlling the alteration of autophagic flux via the Pik3r1-AKT-mTOR axis, and lastly altering osteoclast formation in vitro. In addition, knockdown and overexpression of GSTP1 in vivo also altered bone loss outcomes in the OVX mice model. In general, this study identified a new mechanism by which GSTP1 regulates osteoclastogenesis, and it is evident that the cell fate of osteoclasts is controlled by GSTP1-mediated S-glutathionylation via a redox-autophagy cascade.

Automated summary

Based on genetic associations, GSTP1 may be associated with bone mineral density. This study investigated how GSTP1 affects bone homeostasis through in vitro and in vivo experiments. It was discovered that GSTP1 regulates osteoclast formation by altering autophagic flux via the Pik3r1-AKT-mTOR axis. This study provides a new mechanism for understanding the role of GSTP1 in osteoclastogenesis.