<b>Deletion of 12/15-Lipoxygenase Preserves Retinal Thickness and Function and Selectively Restores Dysregulated microRNAs in Experimental Diabetes Mice</b>

<jats:p>&lt;p dir="ltr"&gt;Diabetic retinopathy (DR) remains a leading cause of blindness, characterized by progressive neurovascular dysfunction. While the enzyme 12/15-lipoxygenase (12/15-LO) and its metabolites are upregulated in DR, their interactions with epigenetic regulators, such as microRNAs (miRNAs), are poorly understood. This study investigates the role of 12/15-LO in miRNA dysregulation and its functional consequences in a type 1 diabetic mouse model. We generated 12/15-LO knockout (KO) mice on an &lt;i&gt;(Ins2&lt;/i&gt;&lt;sup&gt;&lt;em&gt;+/akita&lt;/em&gt;&lt;/sup&gt;&lt;i&gt;)&lt;/i&gt; (Akita) background. Retinal miRNAs expression was profiled using microarray analysis, and retinal structure and function were assessed using histology and electroretinography (ERG). Our results demonstrate that diabetes induces significant dysregulation of a distinct subset of retinal miRNAs (e.g., downregulation of miR-329-3p and miR-431-5p; upregulation of miR-3078-3p and miR-323-5p). Deletion of 12/15-LO prevented diabetes-induced miRNA dysregulation, retinal thinning, and loss of neuronal markers (NeuN and SCGN). Functionally, 12/15-LO&lt;sup&gt;-/-&lt;/sup&gt; rescued diabetes-induced deficits in retinal ganglion cell (pSTR), cone-bipolar cell (photopic b-wave), and cone pathway function (response to natural noise) responses. In conclusion, our findings establish 12/15-LO as a critical upstream regulator of miRNA in the diabetic retina and demonstrate that its deletion protects against neuronal damage in DR. Thus, targeting the 12/15-LO pathway may represent a novel therapeutic strategy to mitigate neuronal dysfunction associated with DR progression.&lt;/p&gt;</jats:p>