**1. Introduction**

Hepatic fibrosis is the excessive accumulation of connective tissue proteins, particularly collagens, in the liver extracellular matrix [1]. This process is the result of chronic liver injury that may be of different aetiologies: viruses, ethanol, toxins, drugs, or cholestasis [1]. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with a prevalence of 20 to 40% in the general population and up to 95% in subjects with obesity and diabetes [2]. NAFLD is characterized by an abnormal accumulation of fatty acids into hepatocytes and includes a wide spectrum of liver diseases, ranging from mild to severe steatosis and non-alcoholic steatohepatitis (NASH) [3]. Both NAFLD and NASH have the potential to evolve into liver fibrosis and cirrhosis. Liver fibrosis involves multiple cell types and molecular mechanisms and processes. Hepatocellular injury unleashes a complex inflammatory response and the release of a plethora of cytokines and growth factors that, on one hand, trigger transformation of quiescent hepatic stellate cells (HSC) into myofibroblast-like cells and, on the other hand, stimulate inflammation and angiogenesis [4]. Chronic inflammation and the long-term injury and regeneration processes perpetuate liver fibrosis and eventually results in distortion of lobular architecture, nodular formation, and cirrhosis [5]. Documented reversibility of advanced liver fibrosis in patients [6–8] has encouraged research on

anti-fibrotic drugs and novel therapeutic strategies [9–15], which are effective in experimental models of liver fibrosis, but their utility in humans is still unknown. Most strategies aimed at interfering with liver fibrosis focus on the inhibition of HSC activation, the modulation of inflammatory response, or the reduction of hepatocyte damage by targeting and modulating multiple cell signalling pathways [4]. Two of these signalling pathways, which have significant impact on the pathophysiology of liver fibrosis, are the endocannabinoid and apelin systems. Patients with advanced liver disease show high circulating levels of both endocannabinoids and apelin, and their respective signalling pathways appear to be upregulated in advanced liver disease [16–18].

This review focuses on recent advances in elucidating the roles of the endocannabinoid and apelin systems in liver fibrosis and their potential clinical relevance. We emphasize recent findings regarding the cellular and molecular mechanisms by which these endogenous systems are involved in liver fibrosis.
