HMGB1 Modulates Decidualization Through PGC1α and Mitochondrial Bioenergetics

Endometrial decidualization is pivotal for embryo implantation and pregnancy. This study explores the role of HMGB1 in endometrial stromal cells (hESCs) during decidualization. We found that HMGB1 expression increased during decidualization in normal tissues but decreased in recurrent spontaneous abortion (RSA) cases. HMGB1 knockdown in hESCs disrupted decidualization by impairing cell differentiation, reducing the expression of prolactin (PRL) and IGFBP1, and increasing abnormal cell proliferation. RNA-seq identified 1,838 differentially expressed genes, among which multiple genes involved in mitotic cell division, reproductive process and oxidative phosphorylation. Mitochondrial dysfunction was evident, with reduced oxidative phosphorylation, ATP production, and mitochondrial fission/fusion balance in HMGB1-deficient cells. CUT&RUN analysis revealed that HMGB1 binds to the PGC1α promoter, a key regulator of mitochondrial biogenesis, suggesting that HMGB1 controls cellular bioenergetics. Finally, PGC1α downregulation in RSA decidua implies that HMGB1 exerts its effects on decidualization through mitochondrial regulation. These findings highlight HMGB1’s critical role in orchestrating mitochondrial function and cellular energy homeostasis during decidualization, offering new insights into the molecular mechanisms behind decidual dysfunction and pregnancy disorders. To investigate the mechanism of HMGB1 during endometial decidualization, we utilized the human endometrial stromal cell line hESCs and constructed a Hmgb1 knockdown cell line using shRNA lentivirus. Then we induced decidualization in knockdown and control cells for 7 days using a combination of cAMP and MPA treatment.