GSK3β‐Regulated Lipolysis is Required for Histone Acetylation and Decidualization in Early Pregnancy

Decidualization, a highly programmed differentiation process of the uterine stroma, is characterized by significant biochemical remodeling and is essential for pregnancy. However, the functions and molecular mechanisms of lipid metabolism during decidualization remain poorly understood. In this study, a dynamic process of lipid droplet synthesis and degradation is observed during decidual progression, and GSK3 is identified as a potential regulator for lipolysis. Specifically, lipolysis is inhibited in uterine Gsk3b knockout mice, leading to impaired terminal differentiation of decidual cells. Mechanistically, GSK3β promots phosphorylation-dependent lysosomal degradation of RNF213, which permits the localization of adipose triglyceride lipase (ATGL) on lipid droplets, thereby facilitating lipolysis. Furthermore, fatty acids released from lipolysis enter the mitochondria to undergo β-oxidation and produce acetyl-CoA. The inhibition of lipolysis caused by GSK3β deficiency leads to a reduction in acetyl-CoA levels, which in turn epigenetically affects gene transcription through histone acetylation. This study provided evidence for the regulation of dynamic lipid metabolism in vivo, and its influences on gene transcription for decidualization, which emphasized the critical role of metabolic modulation in uteri during early pregnancy.