FYN x GSK-3β

The lack of efficient treatments and reliable biomarkers for neurodegenerative diseases requires the development of a late-stage powerful therapy. To this aim, we focused on Fyn and GSK-3β because both kinases are strictly involved in regulating neurodevelopmental processes, besides orchestrating neurotoxic aggregates' deposition and neuroinflammatory processes development. Based on these premises, we developed dual kinase inhibitors to verify at the cellular level the suitability of Fyn and GSK-3β modulation in pursuing the recovery of neural trophism paired to the activation of a neuroprotective profile. Starting from the mild inhibitory potency of the 3-aminothiazole-7-azaindole scaffold, we identified nanomolar dual and selective inhibitors among the kinases of interest. In-depth biological evaluations were performed with the best compounds of the series to assess the neuroprotective and neuromodulatory properties, like enabling neurogenesis or glial polarization, as well as triggering immunomodulation with different patterns relating to their inhibitory profile, setting the stage for potential development of neuroregenerative treatments.

The online version contains supplementary material available at 10.1007/s13205-025-04413-3.

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.

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.

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.

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.