Therapeutic\nEfficacy of a Synthetic Brain-Targeted\nH<sub>2</sub>S Donor Cross-Linked Nanomicelle in Autism Spectrum Disorder\nRats through Aerobic Glycolysis

Autism spectrum disorder (ASD) is\ncharacterized by cognitive inflexibility\nand social deficits, with a notably limited range of brain-targeted\nmedications, particularly in the field of nanomedicine. Herein, we\nintroduce the brain-targeted H<sub>2</sub>S donor cross-linked nanomicelle,\nnamed mannose-PEG600-lipoic acid (Man-LA). Man-LA demonstrates enhanced\nstability and precise brain delivery by interacting with glucose transporter\n1 (GLUT1) in astrocytes, facilitating a gradual release of H<sub>2</sub>S that is modulated by glutathione (GSH). <i>In vivo</i>, studies suggest that Man-LA alleviates symptoms of ASD, correlating\nwith increased expression of aerobic glycolysis enzymes, elevated\nlactate production, and higher H<sub>2</sub>S levels, while preventing\ndamage to hippocampal neurons. <i>In vitro</i>, Man-LA tightly\nbinds to aldehyde dehydrogenase family 3 member B1 (<i>Aldh3b1)</i> in astrocytes, upregulating its expression. This interaction promotes\naerobic glycolysis and enhances lactate production. These findings\nsuggest a connection between ASD deficits and the dysregulation of\nastrocytic aerobic glycolysis, underscoring the role of H<sub>2</sub>S. Identifying the <i>Aldh3b1</i> gene within aerobic glycolysis\npathways provides a promising target for ASD treatment.