Hyperactivated Glycolysis Drives Spatially-Patterned Kupffer Cell Depletion in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is characterized by hepatic inflammation and cell death, yet the mechanisms underlying Kupffer cell (KCs) loss remain unclear. This study aims to elucidate metabolic changes behind KCs death. Using metabolomics, immunostaining, and flow cytometry, we evaluated glucose metabolic alterations and KCs death in a MASLD mouse model. Further investigation via immunostaining, Seahorse analysis, and ¹³C-glucose isotopic tracing elucidated the glucose metabolic mechanisms underlying KCs death. Here, we demonstrate that KCs death is a hallmark feature of MASLD progression across multiple dietary models, showing significantly higher susceptibility compared to other hepatic cell types. Through comprehensive metabolic profiling, we reveal that KCs undergo progressive glucose metabolic reprogramming during MASLD development, which is correlated with KCs death. In combination of biochemical agonist, isotope tracing and KCs culture, we further demonstrated that glycolysis metabolism activation directly contributes to KCs death in vitro. Additionally, using genetic ablation of Chi3l1 mouse, we further demonstrated that increased glucose utilization accelerate KCs death in vivo. Our findings establish a correlation between glucose metabolic dynamic changes and KCs death during MASLD progression, suggesting that modulation of glucose metabolic pathways may represent a strategy to prevent KCs death and thereby alleviate MASLD.