Hyperoside alleviates endometrial stromal cell senescence in unexplained recurrent spontaneous abortion via...

Area of Science:

• Reproductive Biology
• Molecular Medicine
• Genomic Stability

Background:

• Decidualization deficiency is a key pathology in unexplained recurrent spontaneous abortion (URSA).
• The molecular mechanisms driving this deficiency and potential therapeutic targets remain largely unknown.
• Hyperoside, a flavonoid, shows promise for URSA treatment, but its mechanism is unclear.

Purpose of the Study:

• To investigate the mechanism of hyperoside in treating URSA.
• To explore the role of R-loop-driven endometrial stromal cell senescence in URSA.
• To identify the molecular targets of hyperoside in the context of URSA.

Main Methods:

• Integrated multi-omics approach using URSA patient tissues, mouse models, and in vitro cell cultures.
• Validation of hyperoside's effects on R-loop accumulation, cellular senescence, and the cGAS-STING pathway.
• Identification and functional validation of DExH-box helicase 9 (DHX9) as a hyperoside target.

Main Results:

• Hyperoside dose-dependently reduced embryo resorption and rescued decidualization deficiency by preventing stromal cell senescence.
• Hyperoside alleviated aberrant R-loop accumulation and suppressed cGAS-STING pathway activation.
• DHX9 was identified as the molecular target, with its Thr419 residue being critical for hyperoside's anti-senescence and pro-decidualization effects.

Conclusions:

• Hyperoside alleviates URSA-associated decidual dysfunction by resolving R-loops via DHX9, thereby suppressing senescence signaling.
• This study highlights R-loop-mediated genomic stress as a significant factor in URSA.
• Hyperoside represents a potential therapeutic agent for URSA by maintaining R-loop homeostasis through DHX9.