Multi-omics analysis and experimental verification reveal testicular fatty acid metabolism disorder in non-obstructive azoospermia

Increasing evidence suggests that disorders of testicular fatty acid metabolism may induce non-obstructive azoospermia (NOA), one of the most severe forms of male infertility. However, the role and mechanisms of fatty acid metabolism in the development of NOA have not been fully elucidated. Here, we employed multi-omics analysis to observe the changes in fatty acid metabolism in NOA, including microarray, single-cell sequencing (scRNA-seq), and metabolomics data from public databases. We found that ACSL6, ACSBG2, and OLAH were linked to fatty acid metabolism disorders and might be causal genes for NOA. Downregulation of omega-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), might contribute to the pathological process of NOA. Furthermore, Sertoli cells showed apparent fatty acid metabolism disorders in NOA patients, and PPARG was identified as a key transcription factor (TF) regulating this process. Subsequent experiments demonstrated that PPARG was crucial for maintaining the integrity of the blood-testis barrier (BTB) and promoting spermatogenesis by regulating fatty acid metabolism. Our study revealed an important role of fatty acid metabolism in NOA and provided PPARG as a potential therapeutic target for NOA.