Puerarin Ameliorates Premature Ovarian Failure by Activation of Mitochondrial Biogenesis, Dynamics, and Mitophagy Through Up‐Regulation of SIRT1

Abstract Premature ovarian failure (POF) is characterized by ovarian atrophy and decreased fertility. Puerarin (Pue), an isoflavone compound, exerts protective effects on ovarian, however, with undefined mechanisms in POF. POF models were established by cyclophosphamide, and Pue and silent information regulator sirtuin 1 (SIRT1) inhibitor Selisistat (EX527) were used. Next, extracted primary rat ovarian granulosa cells (GCs) were treated with EX527 and autophagy activator rapamycin (RA). The data showed that in POF rats, Pue ameliorated estrous cycle, pathological damage, and senescence with higher ovarian index, anti‐Müllerianhormone, estradiol, glutathione peroxidase, superoxide dismutase, mitochondrial DNA, and lower luteinizing hormone and follicle‐stimulating hormone levels. In GCs, Pue increased cell viability, mitochondrial membrane potential, adenosine triphosphate levels, with decreased senescence and reactive oxygen species. Moreover, Pue induced mitophagy, enhanced peroxisome proliferators‐activated receptor‐γ coactivator‐1alpha (PGC‐1α), and reduced malondialdehyde, p16INK4a, p‐adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK)/AMPK, mitochondrial transcription factor A, nuclear respiratory factor 1, dynamin‐related protein 1, and mitochondrial fission 1 expression. Notably, the EX527 addition offset the above effects, while RA further reversed effects of EX527. In conclusion, Pue activated mitochondrial biogenesis, dynamics and mitophagy through up‐regulation of SIRT1/PGC‐1α pathway to ameliorate POF, providing a theoretical support for clinical application of Pue in POF.