2. Academic Validation
  3. GSK3β-Regulated Lipolysis is Required for Histone Acetylation and Decidualization in Early Pregnancy

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

  • Adv Sci (Weinh). 2025 Nov 9:e14291. doi: 10.1002/advs.202514291.
Peiran Wang 1 2,  Yedong Tang 2,  Xueling Zhao 2,  Yu Ni 2,  Hualan Zhou 2,  Enhao Zhang 1 2,  Gaizhen Li 2,  Han Cai 2,  Yinan Wang 2,  James R Woodgett 3,  Wenbo Deng 2,  Haibin Wang 2 4,  Zhongxian Lu 1 5,  Haili Bao 2,  Shuangbo Kong 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2 Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
  • 3 Lunenfeld-Tanenbaum Research Institute, Sinai Health and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1X5, Canada.
  • 4 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
  • 5 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361005, China.
PMID: 41208306 DOI: 10.1002/advs.202514291
Abstract

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.

Keywords

GSK3β; Lipid droplet; decidualization; histone acetylation; lipolysis.

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