Sterile inflammation in MASH: emerging role of extracellular RNA and therapeutic strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), are major global health issues involving metabolic dysfunction, hepatic lipotoxicity, and chronic inflammation. A key driver of MASH pathogenesis is sterile inflammation, a non-infectious immune response triggered by molecules that are released from injured or dying liver cells. These molecules termed as damage-associated molecular patterns (DAMPs), which activate innate immune receptors, such as Toll-like receptors (TLRs), NOD-like receptors, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to encourage inflammatory signaling, cytokine production, immune cell recruitment, and ultimately fibrogenic activation in MASH. Sterile inflammation sits at the crossroads of metabolic injury and immune activation in MASH and drives disease progression from simple fat build-up to irreversible liver damage. Targeting these sterile inflammatory pathways appears to be an attractive approach for halting or reversing hepatic inflammation and fibrogenic activation in MASH. Extracellular RNAs (eRNAs) have recently been identified as potent DAMPs that trigger sterile inflammation in MASH by engaging in TLR3 signaling. Furthermore, RNase1-based treatments have been proposed as novel therapeutic strategies to interrupt the self-sustaining loop of inflammatory signaling induced by eRNA in MASH. In this review, we discuss the key molecular mechanisms that fuel sterile inflammation in MASLD/MASH, highlighting eRNA as novel therapeutic targets to restrict inflammation in MASH.