Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.