Hepatic iron accumulation and toxicity is a frequent finding in chronic liver diseases such as hereditary hemochromatosis (HH), metabolic associated fatty liver disease (MASLD), alcoholic liver disease (ALD) and hepatitis C virus (HCV) infection, however, it's contribution to disease pathology is not fully understood. Here, using HepG2 cells we show that iron induced hepatocyte damage triggers the release of extracellular RNAs (eRNAs), which bind to the toll-like receptor 3 (TLR3), resulting in the production of pro-inflammatory cytokines. Furthermore, the inhibition of eRNA activity by RNase1 and TLR3 inhibitor significantly improved cell viability as well as NLRP3 and NF-kB-mediated inflammatory signalling. Therefore, eRNA antagonism could represent a novel therapeutic approach to reduce iron-induced inflammation in chronic liver diseases.