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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)\u2010induced LD overload in\u00a0vitro replicated these aging phenotypes, triggering ROS overproduction that provoked ribosome collisions and caused decreased protein synthesis globally. Moreover, LD\u2010driven ROS disrupted mRNA translation, particularly at GA\u2010rich sequences encoding aspartate and glutamate. Collided ribosomes activated the ZAK\u03b1\u2010p38 axis in Sertoli cells, causing cellular senescence and impairing the blood\u2010testis barrier. ZAK\u03b1 inhibitor Nilotinib attenuated testicular atrophy, restored testosterone levels, and mitigated Sertoli cells dysfunction in aged mice. Targeting this pathway with ZAK\u03b1 inhibitor offers a therapeutic strategy for age\u2010related gonadal decline, bridging lipid metabolism dysfunction, and reproductive aging.<\/jats:p>","DOI":"10.1111\/acel.70359","type":"journal-article","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T07:26:08Z","timestamp":1767425168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipid Droplet\u2010Driven Ribosome Collisions Trigger\n                    <scp>ZAK\u03b1<\/scp>\n                    \u2010p38 Signaling to Accelerate Testicular Aging"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-2069","authenticated-orcid":false,"given":"Yanghua","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Urology The Fifth Affiliated Hospital, Sun Yat\u2010Sen University  Zhuhai Guangdong China"},{"name":"Department of Interventional Medicine, Guangdong 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