SGK1 inhibits oxidative injury and extracellular matrix degradation by activating the GSK-3β (Ser9)/Fyn/NRF2 pathway in pelvic organ prolapse

Abstract

Aims

Sustained oxidative stress (OS) promotes the development of pelvic organ prolapse (POP); however, the pathogenesis of POP under OS conditions remains unclear. This study aimed to investigate the role of serum and glucocorticoid-induced protein kinase 1 (SGK1) in the progression of POP in OS and elucidate its potential molecular mechanisms.

Materials and methods

The protein levels of SGK1 in fibroblasts and other cells within the uterosacral ligament tissues (ULTs) from patients with POP in OS were measured by immunofluorescence (IF). Human uterosacral ligament fibroblasts (hUSLFs) were treated with hydrogen peroxide (H₂O₂) to establish an in vitro model of oxidative damage. SGK1 was overexpressed and knocked down using a lentivirus to investigate oxidative damage and extracellular matrix (ECM) degradation under H₂O₂ stimulation. The interaction between SGK1 and GSK-3β was explored using co-immunoprecipitation assays, molecular docking models, and IF.

Key findings

SGK1 was upregulated in fibroblasts within the ULTs from patients with POP under OS conditions and in H₂O₂-induced hUSLFs. SGK1 overexpression in H₂O₂-treated hUSLFs inhibited H₂O₂-triggered apoptosis, reactive oxygen species generation, and collagen loss, whereas SGK1 depletion promoted these processes. Mechanistically, SGK1 suppressed OS-induced oxidative damage, and ECM degradation in hUSLFs by binding with GSK-3β to activate the GSK-3β (Ser9)/Fyn/NRF2 pathway.

Significance

Our results revealed that SGK1 could potentially slow down the progression of POP under OS by interacting with GSK-3β to promote the GSK-3β (Ser9)/Fyn/NRF2 pathway, which provides a potential therapeutic approach for treating POP.