Novel association between E3 ubiquitin ligase MARCH8 and glucose transporter Glut1 in intracerebral hemorrhage.

Abstract

BACKGROUND: Intracerebral hemorrhage (ICH) leads to hematoma formation and neuroinflammation, resulting in severe neurological damage, with limited treatment options available. Membrane-associated RING-CH 8 (MARCH8) is known to be involved in inflammatory responses; however, its specific role in ICH remains unclear. This study investigates the function of MARCH8 in ICH, its mechanism in regulating neuroinflammation, and its potential value as a therapeutic target. METHODS: An in vivo ICH model was established using C57BL/6 J mice. Gene and protein expression were analyzed by qRT-PCR, Western blot, and immunofluorescence staining. Neurological functional was evaluated via neurobehavioral tests, and inflammation markers, oxidative stress levels, and protein interactions were examined. RESULTS: After ICH, MARCH8 expression in brain tissues and plasma was significantly downregulated. Overexpression of MARCH8 significantly improved neurological function, alleviated brain edema, suppressed oxidative stress and inflammation, and increased the survival rate of mice. Additionally, MARCH8 was found to co-localized with Glut1 in microglia, promoting Glut1 degradation via the ubiquitin-proteasome pathway, thereby reducing Glut1 stability. CONCLUSION: Our findings highlight the protective role of MARCH8 in ICH, mainly through regulating inflammatory responses, oxidative stress, and Glut1 degradation, suggesting that MARCH8 or its activator could serve as a potential therapeutic target for ICH, offering new insights into treatment strategies for the condition.