Superior neurometabolic protection by 8-hydroxy-dihydromyricetin over dihydromyricetin in diabetic zebrafish: insights from integrated metabolomics and transcriptomics

Herein, the effects of C-8 hydroxylation on the protective properties of dihydromyricetin (DHM) in a zebrafish larval model of diabetes and neurometabolic dysfunction were investigated. Diabetes was induced using alloxan and glucose, followed by treatment with DHM and its hydroxylated form, 8-hydroxy-dihydromyricetin (H-DHM), obtained through <i>Beauveria bassiana</i> fermentation. Biochemical, metabolomic, and transcriptomic analyses were conducted to evaluate their differences in efficacy. The results demonstrated that hydroxylation enhanced DHM's ability to improve locomotor activity, regulate Na⁺/K⁺-ATPase, Ca²⁺-ATPase, acetylcholinesterase, glutamate, and ATP levels, and modulate oxidative stress, as well as glucose and lipid homeostasis in diabetic zebrafish. Metabolomic analysis revealed that both DHM and H-DHM influenced key metabolic pathways, including amino acid metabolism, purine metabolism, and glycerophospholipid metabolism, while H-DHM specifically regulated sphingolipid metabolism. Transcriptomic analysis and weighted gene co-expression network analysis (WGCNA) further indicated that hydroxylation enhanced DHM's ability to target genes associated with pancreatic β-cell function, oxidative stress, and energy metabolism, such as <i>DUSP26</i>, <i>ITLN1</i>, <i>gdf11</i>, <i>insl5a</i>, <i>pik3r5</i>, <i>gck</i>, <i>kcnj1a.6</i>, <i>tfr2</i>, <i>ebi3</i>, <i>KYAT3</i>, and <i>hdac12</i>. The enhancement of DHM's regulatory effects on diabetes-associated neurometabolic dysfunction highlights the potential of fermentation-derived natural product derivatives for chronic disease management.