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 (KC) loss remain poorly understood. Here, we sought to elucidate the metabolic basis of KC death during MASLD. Using metabolomics, immunostaining, and flow cytometry, we evaluated metabolic alterations and KC death throughout early MASLD progression. We found that KC death is an early hallmark of MASLD, exhibiting greater susceptibility and a spatial distribution consistent with KC zonation. Moreoever, KCs undergo progressive metabolic reprogramming toward enhanced glucose utilization during MASLD development, which is correlated with KC death. In combination with biochemical agonist, isotope tracing, and primary KC culture, we further demonstrated that augmented glycolytic metabolism directly drives KC death in vitro. Consistently, using Chi3l1-deficient mice, we further demonstrated that increased glucose utilization accelerates KC death in vivo. Together, these findings establish a causal link between glycolytic activation and KC loss during MASLD progression, highlighting glucose metabolic pathways as potential therapeutic targets to preserve KC homeostasis and mitigate MASLD.