Multidimensional regulation of hepatic macrophages in chronic liver disease: from metabolic reprogramming to...

Chronic liver diseases (CLDs), including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD, viral hepatitis, liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC)), impose enormous global public health burdens. Hepatic macrophages act as core orchestrators governing the initiation and progression of all CLD subtypes. This review systematically integrates recent advances regarding hepatic macrophage ontogeny, spatial heterogeneity, metabolic rewiring, multi-cellular communication, and systemic neuro-immune crosstalk along the gut-liver-brain axis. Beyond the outdated binary M1/M2 classification, tissue-resident macrophages (ResMø) and recruited monocyte-derived macrophages (MDMs) differentiate into disease-specific subsets (LAMs, SAMs, SenAMs) with spatially restricted, context-dependent functions. Metabolic reprogramming-glycolysis for pro-inflammatory polarization versus oxidative phosphorylation (OXPHOS)/fatty acid oxidation (FAO) for tissue-repair phenotypes-serves as the intrinsic molecular switch shaping macrophage effector profiles. Extrinsically, bidirectional signaling between hepatic macrophages and hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and other intrahepatic immune cells dictates the balance between hepatic injury and tissue regeneration. Macrophage-derived autophagy, LC3-associated phagocytosis (LAP), and exosomal cargo transfer represent pivotal functional executors mediating intercellular signal transmission. Furthermore, gut microbial metabolites and bidirectional liver-brain neuroimmune signals converge on hepatic macrophages, linking local hepatic inflammation to systemic metabolic and neurocognitive complications. This review further summarizes unresolved bottlenecks and translational prospects for macrophage-targeted precision therapy. Collectively, these multi-layered regulatory networks provide a comprehensive theoretical framework for identifying novel therapeutic targets across the full spectrum of CLDs.