Published online Sep 19, 2025. doi: 10.5498/wjp.v15.i9.109363
Revised: May 23, 2025
Accepted: July 14, 2025
Published online: September 19, 2025
Processing time: 105 Days and 20.7 Hours
This article discusses a study by Li et al, which investigates the role of the microglial voltage-gated proton channel 1 (Hv1) in diabetes-related cognitive decline. The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory, reduces microglial production of interleukin-1β and tumour necrosis factor alpha, and decreases apoptosis of oligodendrocyte progenitor cells. Furthermore, electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice, remaining within normal limits. In addition, Hv1 knockdown mitigated interleukin-1β secretion and suppressed ferroptosis markers (ferritin heavy chain/ferritin light chain, CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78, etc.) in vitro, suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination. We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models, longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.
Core Tip: Building upon the groundbreaking work by Li et al who demonstrated that microglial voltage-gated proton channel 1 knockout effectively mitigates neuroinflammation, preserves myelin integrity, and rescues memory deficits in diabetic mouse models, our suggestions focus on advancing this research trajectory. We propose implementing longitudinal assessments to track chronic impacts, utilizing cell-type-specific approaches for mechanistic clarity, and pursuing pharmacological translation for therapeutic potential. To systematically guide these efforts, we provide structured tabulated overviews detailing the study’s strengths, acknowledging its inherent limitations, and outlining specific strategic research pathways for future investigation.