Hepatic Stellate Cells: Fibrogenic Effectors to Central Regulators of Metabolism, Liver Disease Signaling, and Systemic Crosstalk

Hepatic stellate cells (HSCs) have long been regarded as the core effector cells in liver fibrosis. The advent of single-cell omics and metabolomics has led to a paradigm shift in our understanding of these cells. Notably, they are not only implicated in local fibrosis but are being increasingly recognized as a hub integrating metabolic and immune signaling. Located at the interface between hepatic vasculature and parenchyma, HSCs have the capacity to modulate intestinal barrier function, neurotransmitter circulation, myocardial energy metabolism, and bone remodeling through metabolic reprogramming (enhanced glycolysis, vitamin A consumption, glutamine metabolism remodeling) and receptor signaling (TLR4, TGF-β, CXCR4, etc.), as well as by secreting metabolites, exosomal miRNAs, and cytokines. Concurrently, HSCs perceive feedback signals from these organs, forming a dynamic cross-organ feedback network. This review systematically integrates the metabolic characteristics of HSCs in diseases such as metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, chronic viral hepatitis, and hepatocellular carcinoma, along with their cross-organ interactive effects. We further discuss intervention strategies targeting metabolic pathways, exosomal cargo, and the microbiota-metabolism axis, and propose a three-tier translational framework stratifying HSC-targeted therapeutic approaches by developmental stage, offering novel insights for shifting liver disease treatment from single antifibrotic approaches toward systemic, multi-organ precision interventions.