Diminished ovarian reserve (DOR) is a reproductive endocrine disease that causes impaired female fertility due to a reduction in the number and/or quality of oocytes (Penzias et al., 2020). In the clinic, DOR is characterized by low anti-Müllerian hormone (AMH) levels, low antral follicle count (AFC) and elevated basal follicle-stimulating hormone (FSH) levels. To date, the pathogenesis of DOR remains unknown. Multiple factors have been identified as etiologies of DOR (Ge et al., 2019; Greene et al., 2014), including genetics, environment, immunity, infection and aging. The clinical heterogeneity of DOR makes it difficult to diagnose and treat.

Reproductive performance mainly depends on the physiological activity of the follicle, the core unit of the ovary. Cell-cell communications between oocytes and surrounding somatic cells in follicles play an important role in folliculogenesis. Granulosa cells are the main cell type in follicles communicating with oocytes directly, and respond to FSH simulation by expressing the FSH receptor and producing estradiol (E2) to maintain regular, cyclic menstrual cycles. It has been reported that excessive apoptosis of human granulosa cells contributes to the occurrence of DOR (Fan et al., 2019; Bulgurcuoglu Kuran et al., 2022). Utilization of growth hormone (GH) and dehydroepiandrosterone (DHEA) could improve ovarian function by increasing the anti-apoptotic ability of granulosa cells (Jiang et al., 2020; Chang et al., 2022). These studies indicate that abnormal granulosa cell physiological functions may lead to DOR. Therefore, the exploration of the underlying molecular mechanism involved in granulosa cell dysfunction in patients with DOR will be beneficial for the diagnosis and treatment of DOR.

The homeobox (HOX) genes comprise a family of molecules that encode highly conserved transcription factors (Krumlauf, 2018). Several HOX genes are essential for the development of the female reproductive tract, including HOXA9-13 (Du and Taylor, 2016). Previous studies have demonstrated that alternations in HOXA10 and HOXA11 expression are related to several infertility-related diseases, such as endometriosis, polycystic ovarian syndrome, leiomyoma, and hydrosalpinx (Taylor, 1999; Cermik et al., 2003; Sinclair et al., 2011; Daftary et al., 2007). Meanwhile, mutations in the homeobox (NOBOX) gene cause premature ovarian failure (POF) (Qin et al., 2007), indicating the potential role of HOX genes in female reproduction. Homeobox gene A1 (HOXA1), a member of the HOX gene family, has been reported to participate in tumorigenesis and decreased expression of HOXA1 could induce cell apoptosis in several types of cancer cells (Belpaire et al., 2022; Liu et al., 2021; Li et al., 2019; Feng et al., 2021; Wei et al., 2021). However, whether the aberrant expression of HOXA1 is involved in the apoptosis of granulosa cells in patients with DOR remains elusive.

In the present study, we identified aberrant decreased expression levels of HOXA1 in human granulosa cells from patients with DOR. We found that HOXA1 was a gonadotropin response gene and that knockdown of endogenous HOXA1 expression impaired human granulosa cell mitochondrial functions and subsequently promoted cell apoptosis. Our results highlight the potential role of HOXA1 in the occurrence of DOR and provide new insight for the treatment of DOR.