Kupffer cells in liver homeostasis and disease: from immune sentinels to metabolic gatekeepers

The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harbours diverse non-parenchymal cell populations, including immune cells. Among these, Kupffer cells, the resident macrophages of the liver, are critical modulators of liver function and immunity. Emerging research highlights their dynamic roles throughout life, from maintaining tissue homeostasis to shaping the balance between immune tolerance and activation in adulthood. Kupffer cells are located in liver sinusoids, where they act as frontline defenders, clearing pathogens and cellular debris from the circulation. Beyond their established phagocytic and immune regulatory functions, Kupffer cells influence metabolic processes, tissue repair and oncogenesis. Moreover, they shape the response of the liver to metabolic disorders such as metabolic dysfunction-associated steatohepatitis, infections and malignancies, including hepatocellular carcinoma. Here we explore Kupffer cell biology, focusing on the development, heterogeneity and multifaceted roles of these cells in liver health and disease. We further discuss how advances in imaging, transcriptomics and macrophage-targeted therapies can inform future strategies to combat liver-associated health challenges.