Krüppel-like factor 12 regulates aging ovarian granulosa cell apoptosis by repressing SPHK1 transcription and...

Area of Science:

• Reproductive biology
• Cellular and molecular biology
• Gerontology

Background:

• Oxidative stress from aging, radiation, or inflammation causes granulosa cell (GC) apoptosis, impairing ovarian function.
• The precise molecular mechanisms driving GC apoptosis remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanism of oxidative stress-induced GC apoptosis in aging ovaries.
• To investigate the roles of Krüppel-like factor 12 (KLF12) and sphingosine-1-phosphate/sphingosine kinase 1 (SPHK1) in this process.

Main Methods:

• Analysis of oxidative stress markers, reactive oxygen species (ROS) activity, and gene/protein expression (KLF12, SPHK1) in GCs from aging patients.
• In vitro studies using hydrogen peroxide-treated GCs and in vivo models with 3-nitropropionic acid.
• Gene knockdown of KLF12 and functional studies of SPHK1, including variants with deleted KLF12 promoter binding regions.

Main Results:

• Aging ovarian GCs exhibit increased oxidative stress, ROS activity, and decreased SPHK1, alongside significantly elevated KLF12.
• KLF12 upregulation was observed in both in vitro and in vivo models of ovarian oxidative stress.
• KLF12 directly inhibits SPHK1, promoting GC apoptosis. Knockdown of KLF12 or SPHK1 supplementation (especially with intact KLF12 binding) rescued apoptosis.

Conclusions:

• KLF12 plays a critical role in mediating oxidative stress-induced apoptosis in aging ovarian GCs.
• Sphingosine-1-phosphate/SPHK1 exerts a protective effect against GC apoptosis by negatively regulating KLF12.
• Targeting the KLF12-SPHK1 interaction may offer therapeutic strategies for ovarian aging.