The Multicomponent Medicinal Product Hepar Compositum Reduces Hepatic Inflammation and Fibrosis in a Streptozotocin- and High-Fat Diet-Induced Model of Metabolic Dysfunction-Associated Steatotic Liver Disease/Metabolic Dysfunction-Associated Steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD)-formerly known as non-alcoholic fatty liver disease (NAFLD)-is the most common chronic liver disease worldwide. Since there is currently no approved pharmacotherapy for MASLD, there is an urgent unmet need for efficacious therapeutics for this disease. Hepar compositum (HC-24) is a multicomponent medicinal product that consists of 24 natural ingredients. It has been shown to have anti-inflammatory properties in an obesity-associated MASLD mouse model, but its potential to reduce MASLD-associated fibrosis had not been explored before this study. Here, we investigated the hepatic anti-inflammatory and anti-fibrotic potential of HC-24 in a streptozotocin (STZ)- and high-fat diet (HFD)-induced model of MASLD. Mice received a single injection of low-dose STZ at 2 days of age, followed by HFD feeding from 4 to 9 weeks of age. Mice were treated every second day with HC-24 or daily with the positive control telmisartan from 6 to 9 weeks of age. A non-diseased control group was included as a healthy reference. An explorative small-scale pilot study demonstrated that HC-24 improved liver histology, resulting in a lower NAFLD activity score and reduced liver fibrosis. A subsequent full study confirmed these effects and showed that HC-24 reduced hepatic inflammation, specifically reducing T helper cell and neutrophil influx, and decreased hepatic fibrosis (with qualitatively reduced collagen type I and type III immunopositivity) in the absence of an effect on body and liver weight, blood glucose or liver steatosis. These results show that HC-24 has hepatoprotective, anti-inflammatory, and anti-fibrotic properties in an STZ- and HFD-induced model of MASLD/MASH, suggesting that this multicomponent medicine has therapeutic potential for MASLD patients.