Selenium–GPX4 Axis Relieves Arachidonic Acid-Induced Sperm Damage

Selenium (Se) and glutathione peroxidase 4 (GPX4) are essential for male reproduction, regulating spermatogenesis, and resisting peroxidative damage. Arachidonic acid (AA) is closely related to male fertility, but excessive intake adversely affects sperm quality. However, how the Se-GPX4 axis ameliorates AA-induced testicular and sperm injury remains unclear. In this study, an AA-induced sperm injury model was established. Combined with Se supplementation and testicular-specific GPX4 knockout, we measured testicular injury and sperm quality phenotypes and explored the potential mechanism via omics. Results showed that Se supplementation improved AA-induced testicular/sperm damage by regulating GPX4 expression, relieving oxidative stress, apoptosis, sex hormone disorders, and inflammation. Conversely, the GPX4 knockout exacerbated this damage. Oxylipidomics revealed changes in testicular polyunsaturated fatty acid (PUFA) metabolites, while transcriptomics pointed to key pathways. Overall, the Se-GPX4 axis may ameliorate sperm damage by regulating PUFA metabolites, activating glutathione metabolism, alleviating AA-induced testicular oxidative stress, apoptosis and inflammation, and repairing steroid hormone biosynthesis.