Targeting Extracellular RNA Mitigates Hepatic Lipotoxicity and Liver Injury in NASH

Abstract

Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration, and fibrosis, NASH, at a molecular level, involves lipid-induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen for NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage induced by lipotoxicity results in the release of extracellular RNAs (eRNAs), which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravate inflammation, and lead to cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increases cellular viability and reduces NF-kB-mediated cytokine production. Similarly, RNase 1 administration significantly improves hepatic steatosis, inflammatory and injury markers in a murine NASH model. Therefore, this study, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.

Targeting nuclear receptors for NASH/MASH: From bench to bedside

“…The injured or dying hepatocytes release several damage-associated molecular patterns (DAMPs), which upon binding to DAMP receptors on macrophages and hepatic stellate cells (HSCs), trigger these cells to adopt an activated phenotype, thereby leading to inflammation and fibrosis in the liver, which is a hallmark of MASH. 7 , 8 Presently, there are no approved pharmacological treatments for MASH, and lifestyle modification remains the sole available option for its management. This review outlines the current understanding of nuclear receptors (NRs) function in the liver, their dysregulation in MASH, and the therapeutic targeting to counter MASH pathogenesis.…”