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Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.

The liver is one of the most complex organs of the human body and is involved in various metabolic processes. Due to its anatomical proximity to the digestive tract, its blood flow, and its contribution to the detoxification process, the liver is susceptible to a wide variety of disorders. Hepatic diseases can be caused by alcoholism, viral infections, malnutrition and xenobiotics, which result in a high frequency of patients with liver disease and subsequent increase in the number of deaths from these diseases, for which adequate treatments are not yet available. Therefore, the search for new alternatives to treat these liver conditions is mandatory. In recent decades, there has been an increase in interest in medicinal herbs due to their safety and hepatoprotective properties that arise from their anti-inflammatory, antioxidant, antifibrotic, antiviral, immunomodulatory and anticancer properties. Epidemiological and clinical studies have shown that the consumption of these compounds is associated with a decrease in the risk of developing liver diseases; thus, medicinal herbs have emerged as a viable option for the treatment of these hepatic pathologies. However, more basic and clinical studies are needed before reaching a final recommendation to treat human liver diseases. This review provides molecular and clinical information on some natural compounds and medicinal herbs that have hepatoprotective effects and could be useful for the treatment of hepatic disorders.