GHSR‐Foxo1 Signaling in Macrophages Promotes Liver Fibrosis via Inflammatory Response and Hepatic Stellate Cell Activation

Liver fibrosis is a severe liver disease directly linked to chronic inflammation, in which hepatic macrophages play a key role. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin that has essential functions in metabolism, inflammation, and wound-healing. However, the role of GHSR in liver fibrosis is unknown. This study uses a carbon tetrachloride (CCl₄)-induced liver fibrosis mouse model to investigate the role of macrophage GHSR in liver fibrosis. CCl₄ induces macrophage accumulation and inflammatory responses, noticeably increases GHSR expression in the liver. It is found that macrophage Ghsr deletion (Ghsr-MϕKO) attenuates CCl₄-induced liver fibrosis and inflammation, showing reduced hepatic monocyte-derived macrophages (MDMs) and suppressed proinflammatory responses. In macrophages, transforming growth factor (TGF)-β1 expression is positively correlated with GHSR expression. GHSR-associated TGF-β1 in macrophages activates hepatic stellate cells (HSCs) by promoting the crosstalk between macrophages and HSCs. Macrophage GHSR controls inflammation and TGF-β1 expression via protein kinase A (PKA)-mediated Forkhead box protein O 1 (Foxo1) phosphorylation at S273; Foxo1-S273D mutation, mimicking constitutive phosphorylation of Foxo1 at S273, shows exacerbated CCl₄-induced liver inflammation and fibrosis. Thus, targeting the macrophage GHSR-Foxo1 signaling may provide a new strategy to treat liver fibrosis.