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Using two mammalian animal models, we demonstrate that both genetic and pharmacological enhancement of mitochondrial fission (inducing mitochondrial fragmentation) exacerbates collagen loss and accelerates axial elongation, whereas genetic and pharmacological inhibition of mitochondrial fission prevents collagen degradation and attenuates myopia progression. Hypoxia-induced FMT in cultured human scleral fibroblasts (HSFs) requires activation of mitochondrial fission, revealing overproduction of reactive oxygen species (ROS) as the downstream effector on HSFs and in both animal models. Our multilevel analyses identify the mitochondrial fission-ROS axis as a key pathway linking scleral hypoxia to ECM remodeling. Lycopene, a naturally occurring carotenoid antioxidant, significantly attenuated scleral ROS levels and was found suitable for long-term application, highlighting its potential as a therapeutic agent for myopia control. Collectively, these findings have identified a therapeutic target and agent for controlling myopia progression.<\/jats:p>","DOI":"10.1073\/pnas.2511427123","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T17:38:23Z","timestamp":1781113103000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Drp1-driven fragmentation of scleral mitochondria promotes myopia development"],"prefix":"10.1073","volume":"123","author":[{"given":"Zhenqi","family":"Guan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rd5t069","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University","place":["Wenzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Unit of Myopia 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