Obesity impairs spermatogenesis via Leydig cell ferroptosis induced by liver-derived exosomal miR-122-5p

Obesity increases the risk of male infertility, primarily attributable to reduced testosterone levels. Exosomes, which facilitate intercellular communication during reproduction, may influence this process. However, the relation between exosomal cargo changes and high-fat diet (HFD)-induced testosterone decrease remains unclear. Here, we show that exosomes influence testosterone synthesis and spermatogenesis in HFD mice. Transferring exosomes derived from the serum of HFD mice to mice fed a normal diet decreases testosterone levels and sperm counts. Treatment with inhibitors of exosomes (GW4869) and ferroptosis (Ferrostatin-1) rescue HFD-induced impaired spermatogenesis. Additionally, elevated miR-122-5p levels in serum exosomes from HFD mice was partially attributed to increased hepatic miR-122-5p expression. Exosomal miR-122-5p induces ferroptosis in Leydig cells by inhibiting stearyl-CoA desaturase 2 expression, reducing testosterone synthesis and impairing spermatogenesis. Collectively, these findings highlight the impact of liver-derived exosomal alterations on testosterone production in HFD, revealing a regulatory pathway in the liver-testes axis.