Atorvastatin improves spermatogenesis in murine and in vitro human chronic orchitis models through restoring blood-testis barriers.

Chronic orchitis, which stems from autoimmune responses and infections, significantly impairs the testicular niche and affects male fertility. However, there is a lack of effective therapeutic drugs. In this study, we aimed to explore whether atorvastatin can be used for the treatment of chronic orchitis and the underlying mechanism based on our previous findings and detection using the database. We utilized mouse models of chronic orchitis induced by both autoimmune and infectious causes to demonstrate that atorvastatin can markedly improve spermatogenesis and fertility. Mechanism studies through single-cell transcriptomic analysis, target gene knockdown, quantitative proteomics, and small molecule interference revealed that atorvastatin suppressed the Rac1/AP1/MMPs pathway via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in Sertoli cells, thereby restoring the blood-testis barrier (BTB) and spermatogenesis. More importantly, atorvastatin also re-established the expression of BTB-associated proteins and increased the germ cell numbers in cultured human testis tissues. Collectively, our study reveals the essential impact of atorvastatin in improving spermatogenesis in murine and human chronic orchitis models through restoring BTB and suggests that atorvastatin as a promising agent for the clinical treatment of chronic orchitis.