Novel PGK1 determines SKP2-dependent AR stability and reprograms granular cell glucose metabolism facilitating...

Area of Science:

• Reproductive biology
• Molecular endocrinology
• Metabolic disorders

Background:

• Disordered folliculogenesis and hyperandrogenism are hallmarks of Polycystic Ovary Syndrome (PCOS).
• Androgen receptors (ARs) are implicated in PCOS pathogenesis, but their novel binding partners remain underexplored.
• The role of phosphoglycerate kinase 1 (PGK1) in granulosa cells (GCs) in PCOS etiology is unclear.

Purpose of the Study:

• To investigate the role of PGK1 as a novel AR binding partner in the pathogenesis of PCOS.
• To elucidate the molecular mechanisms by which PGK1 influences GC function and PCOS development.
• To identify potential therapeutic targets for PCOS based on the PGK1-AR interaction.

Main Methods:

• Co-immunoprecipitation (co-IP) to identify and confirm PGK1 as an AR binding partner in luteinized GCs.
• Quantitative real-time PCR (qRT-PCR) and Western blotting to assess PGK1 expression.
• In vivo rescue assays in PCOS-like mice, metabolism assays, AR protein stability assays, and RNA-sequencing (RNA-seq) to determine PGK1 function.

Main Results:

• PGK1 and AR are upregulated in PCOS GCs and ovarian tissues.
• PGK1 exacerbates metabolic dysfunction in PCOS-like mice by regulating glucose metabolism.
• PGK1 stabilizes AR by inhibiting ubiquitination, promotes AR nuclear translocation, and regulates ovulation-related genes via the PGK1-AR axis.

Conclusions:

• PGK1 plays a critical role in PCOS pathogenesis by modulating GC metabolism, AR stability, and the expression of key ovulation genes.
• The PGK1-AR axis is a significant contributor to PCOS etiology, affecting cell proliferation and apoptosis.
• PGK1 represents a novel therapeutic target for PCOS, offering a new avenue for treatment.