Abstract

--- - Hepatic fibrosis is a progressive pathological condition characterized by chronic inflammation and excessive extracellular matrix deposition (ECM), which may progress to cirrhosis and liver failure. Although specialized pro-resolving lipid mediators have emerged as potential therapeutic agents, their role in advanced hepatic fibrosis remains incompletely defined. This study aimed to determine whether Maresin 1 (MaR1), an endogenous pro-resolving lipid mediator, promotes the resolution of hepatic fibrosis and modulates the associated inflammatory response. Hepatic fibrosis was induced in mice and rats using diethylnitrosamine (DEN). Animals were subsequently treated with MaR1 or vehicle. Histological and biochemical parameters, apoptosis and proliferation markers, and immune profiles associated with hepatic macrophages polarization were assessed. Additionally, the expression and subcellular localization of retinoic acid related orphan receptor alpha (ROR alpha) and nuclear factor kappa B (NF-kappa B p65) were analysed. MaR1 treatment significantly attenuated hepatic fibrosis, reduced the ECM accumulation, and promoted restoration of liver parenchyma, accompanied by decreased hepatocellular injury and enhanced regenerative capacity. MaR1 also induced immune reprogramming, favouring anti-inflammatory and homeostatic macrophage phenotypes. These effects were associated with increased nuclear activation of ROR alpha and modulation of NF-kappa B signalling pathways. These findings demonstrate that MaR1 promotes the resolution of hepatic fibrosis through macrophage polarization and modulation of the ROR alpha/NF-kappa B axis. This study advances the understanding of pro-resolving mechanisms in hepatic fibrosis and positions MaR1 as a pharmacologically relevant candidate for the development of targeted antifibrotic therapies in chronic liver disease. - Scientific diagram illustrating how Maresin1, administered to mice, promotes the resolution of fibrosis in the liver by reprogramming macrophage polarization and modulating the ROR alpha/NF kappa B pathway to reduce inflammation and inhibit fibrosis-related signals.