MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles.

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (Mir26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of Mir26b in MASH and its therapeutic potential using Mir26b mimic-loaded lipid nanoparticles (LNPs). Apoe, Apoe mice, and respective controls were fed a Western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, Mir26b mimic-loaded LNPs were injected in Apoe mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms. Apoe mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specific Mir26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in Apoe mice. Moreover, Tgfb expression was increased by the Mir26b deficiency, leading to more hepatic fibrosis. A murine treatment model with Mir26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon Mir26b deficiency, which was rescued by LNP treatment. Finally, Mir26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. Overall, our study demonstrates that the detrimental effects of Mir26b deficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology.Fatty liver disease is a condition characterized by the abnormal accumulation of fat in the liver. In certain cases, the fatty build-up can lead to inflammation and, in time, scarring. This advanced stage is known as MASH (short for metabolic dysfunction-associated steatohepatitis), and it can increase the risk of liver failure, cancer, and other complications. Yet the underlying mechanisms that initiate inflammation and thereby drive the disease are still poorly understood. Identifying the molecular factors contributing to this transition could aid in discovering new treatment targets. To explore this question, Peters et al. focus on microRNA-26b, a small molecule involved in many heart and metabolic diseases that helps regulate gene expression. They aimed to clarify the role of microRNA-26b in MASH using mice genetically manipulated to lack this regulatory molecule. The experiments revealed that the animals had larger amounts of fat in their livers, with the organs also showing clear signs of scarring and increased inflammation – including high levels of inflammatory signalling molecules and the presence of immune cells known as macrophages. Peters et al. then treated the animals with specially designed compounds that can act as microRNA-26b. The molecules were safely delivered to the liver within tiny fat-based spheres known as lipid nanoparticles. Following such treatment, the mice showed decreased levels of liver fat and inflammation. The anti-inflammatory effect of the microRNA-26b ‘mimics’ was also confirmed in human liver samples. Together, these results show that microRNA-26b plays a protective role in the development of MASH. Future research should focus on confirming whether these molecules could represent a viable therapeutic treatment, in particular when delivered within lipid-based nanoparticles.