Raza Sana, Tewari Archana, Rajak Sangam, Gupta Pratima, Sinha Rohit A
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
Toxicol Rep. 2025 Jun;14:102002. doi: 10.1016/j.toxrep.2025.102002.
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.
肝铁蓄积和毒性在遗传性血色素沉着症（HH）、代谢相关脂肪性肝病（MASLD）、酒精性肝病（ALD）和丙型肝炎病毒（HCV）感染等慢性肝病中是常见现象，然而，其对疾病病理的作用尚未完全明确。在此，我们利用HepG2细胞表明，铁诱导的肝细胞损伤会触发细胞外RNA（eRNA）的释放，这些eRNA与Toll样受体3（TLR3）结合，导致促炎细胞因子的产生。此外，核糖核酸酶1和TLR3抑制剂对eRNA活性的抑制显著提高了细胞活力以及NLRP3和NF-κB介导的炎症信号传导。因此，拮抗eRNA可能代表一种减少慢性肝病中铁诱导炎症的新型治疗方法。
