Ovarian Rev-erbα: a central regulator of fertility following chronodisruption

Circadian rhythm disruption caused by shift work, nutritional imbalance, and the stresses of modern life can alter hormone secretion, lead to menstrual irregularities, impair follicle development, and contribute to ovarian hypoplasia. The mechanistic role of circadian rhythm disruption in reproductive disorders has been thoroughly investigated. Nuclear receptors are known to play an important role in female reproduction and in maintaining pregnancy. Rev-erbα, a circadian nuclear receptor, is a key component of the circadian clock and helps sustain circadian rhythm.

We evaluated the potential prophylactic and therapeutic functions of Rev-erbα in supporting female fertility by orchestrating a series of events that culminate in successful pregnancy. We generated a circadian rhythm-disrupted female mouse model to study fertility.

The Rev-erbα ligand SR9011 improved the fertility index in these circadian rhythm-disrupted female mice. Moreover, SR9011 treatment restored impaired ovarian follicular cell proliferation and division, regulated steroidogenesis and steroid hormone production, enhanced progesterone and melatonin secretion, and mitigated the adverse effects of circadian disruption on folliculogenesis. SR9011 also reduced follicular atresia and promoted follicle development in CR-disrupted mice. Rev-erbα is a key regulator influencing oocyte retrieval, as demonstrated in mice treated with the Rev-erbα antagonist SR8278.

These findings suggest that targeting Rev-erbα signaling and elucidating its mechanistic role in female reproduction could inform the development of more effective strategies for treating female infertility. As a sought-after druggable target, Rev-erbα has a broad range of potential therapeutic applications and has recently attracted considerable attention in the context of female infertility treatment.