Infertility is a critical worldwide health burden, with 1 in 6 couples currently seeking the help of assisted reproductive technology and at least 50% of infertile cases involving a male factor. This is concerning as there is now compelling evidence that poor sperm quality may be prescient of major systemic diseases such as cardiovascular disease and diabetes. Although many male infertility cases are diagnosed as idiopathic, up to 80% of these cases are underpinned by oxidative stress which drives spermatozoa towards dysfunction and cell death. Despite this knowledge, antioxidant-based strategies have not been clinically successful. Our extensive work examining oxidative damage has led to the discovery of a novel enzyme responsible for its catalysis termed 15-arachidonate lipoxygenase (ALOX15). Importantly, we have demonstrated that the inhibition of ALOX15 can recover the fertilizing-capacity of spermatozoa across multiple species. To build on these important leads this project aims to examine the impact of oxidative stress on cell membranes and determine the efficacy of ALOX15 inhibitors to alleviate lipid peroxidation. Further, we will use a valuable drug-repurposing library and high-throughput phenotypic screening platform to discover clinically relevant compounds that protect sperm cells from oxidative stress. This project will define new strategies to prevent oxidative stress-derived male infertility with implications for human and equine reproductive health.