Puerarin and DHEA combination therapy alleviates primary dysmenorrhea via inhibition of the Hsp90ab1/p38/JNK pathway.

Primary dysmenorrhea (PD), a prevalent gynecological disorder, is fundamentally driven by chronic uterine inflammation, leading to severe lower abdominal pain and recurrent cramping. Given the known anti-inflammatory properties of Puerarin (Pue) and Dehydroepiandrosterone (DHEA), we investigated their individual and combined therapeutic effects on PD using an estradiol benzoate/oxytocin-induced mouse model. Our findings revealed that both Pue and DHEA alleviated PD symptoms, as evidenced by reduced writhing frequency, prolonged inter-writhe intervals, diminished uterine edema, lower uterine PGF2α/PGE2 ratio, decreased levels of inflammatory cytokines, and downregulated endometrial cyclooxygenase-2 (COX-2) expression. Notably, co-administration of Pue and DHEA produced superior therapeutic efficacy. Mechanistically, this combination more effectively reversed the pathological upregulation of Hsp90ab1 and the heightened phosphorylation of p38 and JNK in the PD uterus. However, lentiviral overexpression of Hsp90ab1 significantly attenuated the therapeutic benefits conferred by Pue and DHEA. Collectively, these results demonstrated that the synergistic action of Pue and DHEA represents a potent therapeutic strategy for PD, primarily through suppression of the Hsp90ab1/p38/JNK signaling and subsequent mitigation of uterine inflammation, offering a promising avenue for clinical intervention.