Diabetes mellitus (DM) is a metabolic and endocrinological disorder characterized by high blood glucose levels [1]. It is becoming increasingly prevalent, with a projected 640 million people expected to have diabetes by 2024, and causing 1.5 million deaths every year [2,3]. Nearly all organs such as kidney, heart, retina as well as testis tissues could be affected by DM [[4], [5], [6], [7]]. Growing evidence shows that an increasing number of diabetic males of reproductive age have infertility complications [8], such as reduction in semen quality, disturbance of spermatogenesis as well as increases in oxidative stress and apoptosis in testis [9,10]. Thus, exploring the mechanism of diabetic male infertility is essential to provide targets for diabetic male infertility.

As a common complication among diabetis, diabetic male infertility could be caused by many potential mechanisms. The loss of spermatogenic cells is a potential contributing factor in the development of diabetic male infertility [11,12]. Increased oxidative stress levels, disruptions in the hypothalamic-pituitary-gonadal axis, and impaired blood-testis barrier (BTB) all could cause the diminish of spermatogenic cells [[13], [14], [15], [16]]. Apoptosis and autophagy also play important roles in the development of diabetic male infertility [17,18]. However, the underlying mechanisms of diabetic male infertility are still incompletely defined, and there are still no effective therapeutic options for these reproductive lesions.

As an emerging form of programmed cell death, ferroptosis, has been implicated in the pathogenesis of various diseases including tumor suppression, immune responses, ischemic organ damage and diabetic nephropathy [[19], [20], [21], [22]]. At the heart of ferroptosis regulation is GPX4, a selenoprotein that transforms phospholipid and cholesterol hydroperoxides to their corresponding alcohol by utilizing reduced glutathione (GSH), thereby protecting cells from oxidative lipid damage [23,24]. It has been indicated that the vital roles of ferroptosis in testicular function. Cadmium, di-(2-ethylhexyl) phthalate and nicotine could induce excessive Heme oxygenase activity, HIF-1α accumulation, release of free iron, lipid peroxidation, and the activation of Bmal1-mediated Nrf2 pathway thus resulted in ferroptosis in the testis [25,26]. Our previous study also demonstrated that 3-hydroxyphenylacetic acid treatment rejuvenated spermatogenic dysfunction of aged mice through GPX4-mediated ferroptosis [27]. However, whether ferroptosis is implicated in diabetic spermatogenic dysfunction remains unclear.

In the present study, we investigated the characteristics of ferroptosis in the spermatogenic dysfunction of diabetic mice models and DM patients. We further explored the roles of ferroptosis in spermatogenic dysfunction by using ferroptosis inhibitor and GPX4 overexpression in diabetic mice and high glucose (HG)-treated GC-2 cells. Our results suggest that increased ferroptosis could result in diabetic spermatogenic dysfunction and ferroptosis may be a promising therapeutic target for diabetic male infertility.