Liquiritin prevents preterm labor by remodeling decidual steroid homeostasis through 11β-HSD1 inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhiza uralensis Fisch. ex DC.) is ethnobotanically indicated for stabilizing pregnancy and alleviating gestational abdominal pain. Its primary flavonoid, liquiritin (LQ), exhibits anti-inflammatory, antioxidant, and steroid-modulatory activities. Whether LQ prevents spontaneous preterm birth (sPTB) by rectifying placental inflammatory-metabolic imbalance remains unknown.

AIM OF THE STUDY: This study investigated the pharmacological efficacy of LQ against sPTB while deciphering the molecular mechanisms.

MATERIALS AND

METHODS

The therapeutic efficacy of LQ was initially assessed in a lipopolysaccharide (LPS)-induced intrauterine inflammation (IUI) murine model, integrating histopathological, transcriptomic, and molecular profiling analyses. Subsequently, the molecular target of LQ was elucidated via DARTS-MS, molecular docking, CETSA-WB, and enzyme activity measurements in human decidual stromal cells (hDSCs). Target dependency was further validated through siRNA-mediated knockdown and overexpression rescue experiments. Finally, the downstream signaling mechanisms were dissected using complementary molecular analyses.

RESULTS

In the LPS-induced IUI murine model, LQ markedly prolonged gestation and enhanced neonatal survival. Mechanistically, LQ recalibrated glucocorticoid-redox homeostasis by suppressing NOX2 expression and activating the Nrf2/HO-1 antioxidant axis. In primary hDSCs, integrated chemoproteomics and biochemical assays identified 11β-HSD1 as a high-affinity functional target of LQ. Mechanistic interrogation confirmed that LQ-mediated 11β-HSD1 inhibition disrupts a pro-inflammatory loop, specifically suppressing cortisol amplification and subsequent COX-2/NOX2 cascades, which in turn reduced prostaglandin production.

CONCLUSION

This study demonstrates that LQ alleviates placental dysfunction by suppressing glucocorticoid excess and the associated pro-inflammatory cascade and identifies 11β-HSD1 as a direct target of LQ in hDSCs, supporting its potential as a metabolic intervention targeting steroid homeostasis for sPTB prevention.