HMGB1 modulates decidualization through PPARGC1A and mitochondrial bioenergetics

Endometrial decidualization is essential for successful embryo implantation and pregnancy establishment. This study investigates the role of high mobility group box 1 (HMGB1) in endometrial stromal cells (hESCs) during decidualization. We found that HMGB1 expression was upregulated during decidualization in vitro and in normal decidual tissues but was reduced in decidua from patients with recurrent spontaneous abortion (RSA). HMGB1 Knockdown in hESCs impaired decidualization by disrupting stromal cell differentiation, reducing the expression of prolactin (PRL) and insulin like growth factor binding protein 1 (IGFBP1), and promoting aberrant cell proliferation. HMGB1 deficiency resulted in mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced ATP production, and altered mitochondrial morphology and membrane potential. Mechanistically, HMGB1 regulated the expression of PPARG coactivator 1 alpha (PPARGC1A), a key regulator of mitochondrial biogenesis and oxidative metabolism, suggesting that HMGB1 contributes to decidualization through PPARGC1A mediated metabolic regulation. Furthermore, reduced PPARGC1A expression in RSA decidua further supports the involvement of the HMGB1-PPARGC1A axis in decidual dysfunction. In addition, HMGB1 exhibited dynamic expression patterns in the uterus of early pregnant mice, with enriched expression in decidual regions at implantation sites. Collectively, these findings identify HMGB1 as an important regulator of decidualization by coordinating mitochondrial function and cellular energy metabolism, providing new insights into the molecular mechanisms underlying decidual dysfunction and pregnancy complications.