The Crosstalk Between Macrophages and Hepatic Energy Metabolic Reprogramming and the Modulation by Natural Products: An Overview

Abstract Hepatic metabolic disorders, characterized by disrupted glucose and lipid homeostasis, are growing global health concerns. While hepatocytes have traditionally been regarded as the primary regulators of metabolic balance, increasing evidence identifies liver macrophages as key mediators that link inflammatory signaling to metabolic reprogramming. Liver macrophages, including Kupffer cells and monocyte-derived macrophages, exhibit dynamic responses to metabolic stress, shifting between pro- and anti-inflammatory states. Through cytokine secretion, redox signaling, and extracellular-vesicle-mediated communication, they modulate hepatocellular metabolism and contribute to metabolic remodeling. Natural products have emerged as promising modulators of energy metabolism and macrophage polarization. Compounds such as polyphenols, coumarins, terpenoids, polyunsaturated fatty acids, and alkaloids regulate key pathways, including AMPK, Nrf2, and PPARs, thereby offering therapeutic potential to restore metabolic homeostasis by targeting macrophages. This Review summarizes these interactions and highlights macrophage-targeted therapeutic strategies.