Background Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1), the ligase of the UFMylation system, has recently been reported to be involved in apoptosis and endoplasmic reticulum stress (ER stress) in a variety of diseases. Premature ovarian failure (POF) is a gynecological disease that severely reduces the fertility of women, especially in female cancer patients receiving chemotherapy drugs. Whether UFL1 is involved in protection against chemotherapy-induced POF and its mechanism remain unclear. Methods In this study, we examined the function of UFL1 in ovarian dysfunction and granulosa cell (GC) apoptosis induced by cisplatin through histological examination and cell viability analysis. We used western blotting, quantitative real-time PCR (qPCR) and immunofluorescence (IF) to detect the expression of UFL1 and the levels of ER stress specific markers. Enzyme linked immunosorbent assays were used to detect the levels of follicle-stimulating hormone (FSH) and estrogen (E2) in ovaries and GCs. In addition, we used infection with lentiviral particle suspensions to knock down and overexpress UFL1 in ovaries and GCs, respectively. Results Our data showed that the expression of UFL1 was reduced in POF model ovaries, accompanied by ER stress. In vitro, cisplatin induced a stress-related increase in UFL1 expression in GCs and enhanced ER stress, which was aggravated by UFL1 knockdown and alleviated by UFL1 overexpression. Furthermore, UFL1 knockdown resulted in a decrease in ovarian follicle number, an increase in atretic follicles, and decreased expression of AMH and FSHR. Conversely, the overexpression of UFL1 reduced cisplatin-induced damage to the ovary in vitro. Conclusions Our research indicated that UFL1 regulates cisplatin-induced ER stress and apoptosis in GCs, and participates in protection against cisplatin-induced POF, providing a potential therapeutic target for the clinical prevention of chemotherapeutic drug-induced POF. Graphical Abstract

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BackgroundUbiquitin-like modifier 1 ligating enzyme 1 (UFL1), the ligase of the Ufmylation system, has recently been reported to be involved in apoptosis and endoplasmic reticulum stress (ER stress) in a variety of diseases. Premature ovarian failure (POF) is a gynecological disease that severely reduces the fertility of women, especially in female cancer patients receiving chemotherapy drugs. Whether UFL1 is involved in the protection from chemotherapy-induced POF and its mechanism remains unclear. MethodsIn this study, we examined the function of UFL1 in ovarian dysfunction and granular cells (GCs) apoptosis induced by cisplatin through histological examination and cell viability analysis. We used western blot, quantitative real-time PCR (qPCR) and immunofluorescence (IF) to detect the expression of UFL1 and the level of ER stress specific makers. Enzyme-Linked Immunosorbent Assays were used to detect the level of Follicle-Stimulating Hormone (FSH) and Estrogen (E2) in ovaries and GCs. In addition, we knocked down or overexpressed UFL1 in ovaries or GCs through infected with lentiviral particle suspensions, respectively. ResultsOur data showed that the expression of UFL1 was reduced in POF model ovaries and was accompanied by the occurrence of ER stress. In vitro, cisplatin induced a stressful increase of UFL1 expression in GCs, and enhanced ER stress, which was aggravated by UFL1 knockdown and alleviated by UFL1 overexpression. Furthermore, the data showed that UFL1 knockdown resulted in a decrease of ovarian follicles number, an increase of atretic follicles, and a decreased expression of AMH and FSHR. Conversely, overexpression of UFL1 reduced the damage of cisplatin to the ovary in vitro. ConclusionsOur research proved that UFL1 regulates cisplatin-induced ER stress and apoptosis of GCs, and participates in the protection from cisplatin-induced POF, providing a potential therapeutic target for clinical prevention of chemotherapeutic drug-induced POF.