Kupffer cells: Orchestrators of liver physiology

As the central metabolic organ, the liver coordinates fundamental biological processes through its specialized cellular architecture and regulatory networks, encompassing metabolism, immunity, and regeneration. Kupffer cells (KCs), the liver-resident macrophages, exhibit functional heterogeneity beyond classical polarization paradigms. Currently, multiple classification systems for KCs have been established utilizing distinct surface markers. However, there is no systematic theoretical framework for the classification of KCs. The strategic positioning of KCs within the hepatic Disse space enables intricate intercellular communication networks with neighboring hepatocytes for coordinated physiological regulation. Their functional plasticity critically regulates systemic iron and metabolic homeostasis, with KC-driven metabolic reprogramming directly influencing hepatic pathophysiology. Furtherly, KC activity shows spatiotemporal regulation by circadian rhythms and nutrient signals, reshaping the liver microenvironment to affect function. This review summarizes advances in liver macrophage biology, highlighting the classification challenges of KCs and their roles in hepatic physiology. Additionally, we discuss how circadian rhythms, aging, diet, and exercise dynamically influence KC functionality, which provides a framework to interpret their regulatory logic and dysfunction in disease.