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Aquaporin\u20104 (AQP4), a water channel abundantly expressed in glial cells, plays a pivotal role in edema formation by regulating water homeostasis. Geranylgeranylacetone (GGA), a clinically approved anti\u2010ulcer drug, functions as a potent and non\u2010toxic inducer of heat shock protein 70 (HSP70) and has recently been implicated in the regulation of aquaporin trafficking. In parallel, the sorting nexin 27 (SNX27)\u2010retromer complex is a key mediator of endosomal sorting and recycling of membrane proteins back to the plasma membrane, thereby maintaining their functional activity. In this study, we demonstrate that retinal I\/R injury triggers altered subcellular localization of AQP4, with enhanced internalization compared with sham retinas. Concomitantly, SNX27\u2010retromer expression was significantly upregulated at both mRNA and protein levels, and biochemical as well as imaging assays confirmed its interaction with AQP4. In a pre\u2010ischemia dosing paradigm (prophylactic), GGA markedly attenuated retinal edema and RGC loss, and promoted the interaction between HSP70 and the SNX27\u2010retromer complex. Importantly, GGA treatment reduced SNX27\u2010retromer expression, thereby limiting AQP4 recycling to the plasma membrane and favoring its lysosome\u2010associated trafficking. These effects were largely reversed by quercetin, a pharmacological inhibitor of HSP70, highlighting an HSP70\u2010dependent mechanism. Together, our findings identify a previously unrecognized role of HSP70 in regulating SNX27\u2010retromer\u2013mediated AQP4 trafficking. By disrupting AQP4 recycling, GGA alleviates early retinal edema following I\/R injury, providing mechanistic rationale for future therapeutic development.<\/jats:p>","DOI":"10.1002\/glia.70184","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:12:36Z","timestamp":1781500356000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Geranylgeranylacetone\u2010Induced\n                    <scp>HSP70<\/scp>\n                    Modulates\n                    <scp>AQP4<\/scp>\n                    Trafficking via\n                    <scp>SNX27<\/scp>\n                    \u2010Retromer to Alleviate Retinal Ischemia\/Reperfusion Injury"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1868-449X","authenticated-orcid":false,"given":"Weijian","family":"Qian","sequence":"first","affiliation":[{"name":"Institute of Neuroscience, Basic Medicine College of 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