HMGB1 Modulates Decidualization Through PPARGC1A and Mitochondrial Bioenergetics

Area of Science:

• Reproductive Biology
• Cellular Metabolism
• Molecular Endocrinology

Background:

• Endometrial decidualization is critical for embryo implantation and pregnancy.
• Recurrent spontaneous abortion (RSA) is associated with decidual dysfunction.
• The molecular mechanisms regulating decidualization require further elucidation.

Purpose of the Study:

• To investigate the role of high mobility group box 1 (HMGB1) in human endometrial stromal cells (hESCs) during decidualization.
• To explore the link between HMGB1, mitochondrial function, and decidualization.
• To examine the HMGB1-PPARGC1A axis in the context of RSA.

Main Methods:

• In vitro decidualization of hESCs with HMGB1 manipulation (knockdown).
• Analysis of gene and protein expression (PRL, IGFBP1, PPARGC1A).
• Assessment of mitochondrial function (oxidative phosphorylation, ATP production, morphology).
• Examination of HMGB1 expression in human decidual tissues and mouse uteri.

Main Results:

• HMGB1 expression is upregulated during decidualization but reduced in RSA decidua.
• HMGB1 knockdown impairs hESC differentiation, reduces PRL and IGFBP1, and increases proliferation.
• HMGB1 deficiency leads to mitochondrial dysfunction and impaired ATP production.
• HMGB1 regulates PPARGC1A, a key metabolic regulator, and this axis is disrupted in RSA.
• HMGB1 shows dynamic expression in pregnant mouse uteri.

Conclusions:

• HMGB1 is a key regulator of endometrial decidualization, essential for mitochondrial function and cellular energy metabolism.
• The HMGB1-PPARGC1A pathway plays a significant role in maintaining metabolic homeostasis during decidualization.
• Dysregulation of HMGB1 contributes to decidual dysfunction and pregnancy complications like RSA.