Kupffer Cell Activation and Inflammatory Progression in MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease, or MASLD, is not only a disorder of hepatic fat accumulation, but also a disease shaped by metabolic stress and immune activation. Among the immune cells involved in this process, Kupffer cells play a central role because they are liver-resident macrophages located at the interface between hepatocytes, gut-derived signals, and systemic metabolic inflammation. Under normal conditions, Kupffer cells help maintain liver homeostasis by clearing pathogens, removing cellular debris, and regulating immune tolerance. In MASLD, however, persistent lipid overload, hepatocyte injury, oxidative stress, endotoxin exposure, and adipose tissue inflammation can shift Kupffer cells toward chronic inflammatory activation. Activated Kupffer cells release cytokines and chemokines such as TNF-α, IL-1β, IL-6, and CCL2, which worsen hepatocyte stress, recruit additional immune cells, and support the transition from simple steatosis to metabolic dysfunction-associated steatohepatitis. Their interaction with hepatic stellate cells also connects inflammation with fibrosis development. This essay discusses Kupffer cell activation as a key mechanism in MASLD progression and argues that the disease should be understood as a dynamic process involving metabolic overload, immune response, failed inflammatory resolution, and fibrotic remodeling. Recognizing the dual role of Kupffer cells may help explain why MASLD progression cannot be reduced to fat accumulation alone.