Lipid Droplet-Driven Ribosome Collisions Trigger ZAKα-p38 Signaling to Accelerate Testicular Aging

Testicular aging, a key feature of late-onset hypogonadism (LOH), is closely associated with Sertoli cells dysfunction. Emerging evidence implicates lipid droplet (LD) accumulation as a hallmark of aging in Sertoli cells, but its role in Sertoli cells senescence and the associated molecular mechanisms are unknown. We found that aging and obesity drove progressive LD accumulation in Sertoli cells, accompanied by mitochondrial dysfunction and ROS overproduction. Palmitic Acid (PA)-induced LD overload in vitro replicated these aging phenotypes, triggering ROS overproduction that provoked ribosome collisions and caused decreased protein synthesis globally. Moreover, LD-driven ROS disrupted mRNA translation, particularly at GA-rich sequences encoding aspartate and glutamate. Collided ribosomes activated the ZAKα-p38 axis in Sertoli cells, causing cellular senescence and impairing the blood-testis barrier. ZAKα inhibitor Nilotinib attenuated testicular atrophy, restored testosterone levels, and mitigated Sertoli cells dysfunction in aged mice. Targeting this pathway with ZAKα inhibitor offers a therapeutic strategy for age-related gonadal decline, bridging lipid metabolism dysfunction, and reproductive aging.