Hepatic stellate cell-derived microfibrillar-associated protein 2 prevents liver fibrosis by regulating extracellular matrix and inflammation.

Microfibrillar-associated protein 2 (MFAP-2) is a crucial component of the extracellular matrix (ECM) microfibrils, yet its role in liver fibrosis remains elusive. : Human tissue arrays and mouse models of fibrosis progression and resolution were used to investigate MFAP-2 expression patterns. deficiency ( ) or overexpression (ov) mice were subjected to carbon tetrachloride (CCl) injection or bile duct ligation (BDL) to induce liver fibrosis. Histological, biochemical, bulk, or single-cell RNA-sequencing (scRNA-seq), proteomics to analyze the matrisome, and studies were conducted. : MFAP-2 was predominantly enriched in activated hepatic stellate cells (HSCs) and upregulated in advanced liver fibrosis. Although ablation had minimal impact on collagen deposition during CCl injection, it significantly delayed fibrosis regression after CCl cessation. The delayed fibrosis regression due to deficiency was likely linked to aggravated intrahepatic inflammation, ECM stabilization, and activated focal adhesion signaling in HSCs. Mechanically, inhibiting HSC-derived enhanced HSC interactions and increased matrisome protein production, while reducing the interaction between HSCs and liver-resident macrophages by decreasing macrophage migration inhibitory factor secretion from HSCs. Additionally, we validated the role of deletion in liver fibrosis using the BDL mouse model, demonstrating a more pronounced effect on fibrosis progression. Adeno-associated virus vector (serotype 6)-mediated overexpression in HSCs conferred protection against liver fibrosis in both models. : This study reveals the compensatory protective effects of HSC-derived MFAP-2 on liver fibrosis and its underlying mechanisms. Enhancing MFAP-2 in HSCs may therefore benefit patients with liver fibrosis.