Zingerone ameliorates ovarian impairment by regulating steroidogenesis and apoptosis in letrozole-treated mouse

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, disrupted folliculogenesis, and subfertility. This study evaluated the therapeutic efficacy of zingerone(4-(4-hydroxy-3-methoxyphenyl)-2-butanone) in a letrozole-induced hyperandrogenised PCOS-like mouse model. Zingerone administration, particularly at 25 and 50 mg/kg, significantly improved ovarian morphology by enhancing follicular development and corpus luteum formation. This was accompanied by increased granulosa cell proliferation (PCNA) and attenuation of apoptosis, evidenced by up-regulation of BCL2 and reduced TUNEL staining. Zingerone reprogrammed ovarian steroidogenesis by reducing circulating testosterone, down-regulating androgen receptor expression, suppressing StAR, and up-regulating aromatase, thereby promoting a shift toward estrogen biosynthesis. Autophagy analysis indicated restoration of autophagic flux, reflected by decreased p62 levels and modulation of Beclin1 and LC3B expression. These coordinated molecular and cellular changes resulted in functional recovery, with significant improvement in fertility and litter size at higher doses (25 and 50 mg/kg). Collectively, zingerone exerts dose-dependent, multi-target effects to restore endocrine, cellular, and autophagic homeostasis, thereby ameliorating ovarian dysfunction in PCOS.