<p>We primarily investigated the correlation between long-term high-fat diet and male infertility, aiming to reveal the potential mechanisms underlying PCSK9-induced spermatogenic dysfunction in this context. Clinical data revealed that infertile male patients typically exhibited hyperlipidemia and significantly elevated serum PCSK9 concentrations. To further explore this, we utilized wild-type C57BL/6 male mice and their homologous PCSK9-deficient mice, adhering to experimental control principles. After administering a high-fat diet to the experimental groups, we observed local testicular changes. Results indicated that the high-fat diet induced elevated PCSK9 levels in both the serum and testes while decreasing expression of ZO-1, a key protein in blood-testis barrier integrity. PCSK9 knockout effectively improved lipid metabolism in mice fed a high-fat diet and preserved blood-testis barrier integrity. Subsequently, we cultured Sertoli cells (TM4 cells) to explored underlying mechanisms under different treatments. Under high-lipid conditions, we discovered that LOX1-another lipid metabolism regulator was affected by PCSK9. PCSK9 increased LOX1 expression and, in turn, LOX1 increased PCSK9 expression. PCSK9 and LOX1 mutually promoted each other’s expression, forming a positive feedback loop that reduced ZO-1 expression. Concurrently, both PCSK9 and LOX1 elevated OxLDL levels and increased TNF-α expression. In summary, the PCSK9-LOX1 feedback loop drives abnormally high OxLDL levels and cellular inflammation, ultimately downregulating the tight junction protein ZO-1 in blood-testis barrier, thereby potentially impairing testicular spermatogenesis.</p>