Alpha-ketoglutarate alleviates Cadmium-induced ferroptosis in association with enhanced mitochondrial function in testes.

Cadmium (Cd), an environmental heavy metal, is recognized as a classic reproductive toxicant that can severely impair the male reproductive system and disrupt testicular testosterone production. Alpha-Ketoglutarate (AKG) is an endogenous intermediate metabolite of the tricarboxylic acid cycle, which is involved in multiple cellular metabolic pathways and serves as an energy donor, amino acid precursor, and epigenetic regulator. Notably, AKG also acts as a key regulator of the oxidative stress response, which is closely associated with its antioxidant capacity and ability to stimulate antioxidant enzymes. Here, we examined the effect of dietary AKG supplementation on Cd-induced reproductive function damage in adult male mice. AKG significantly alleviated Cd-induced reproductive function damage, including testosterone reduction and morphological disruption. Interestingly, AKG decreased the Cd treatment disturbed iron homeostasis, reduced Reactive Oxygen Species (ROS) production, and restored mitochondrial dysfunction in vitro and in vivo. Collectively, these findings indicated that AKG alleviated Cd-induced testicular dysfunction and attenuated testosterone synthesis via inhibiting ferroptosis. It is hoped that this research will contribute to the development of new therapeutic strategies against male infertility.