Title : mRNA platform-based klotho therapy for hepatic injury
Abstract:
Hepatocyte senescence triggers metabolic aberrations that drive the progression of hepatic injury. A critical pathological hallmark of hepatic injury progression is liver fibrosis, characterized by excessive extracellular matrix deposition, which is closely linked to the intracellular accumulation of Reactive Oxygen Species (ROS). Persistent oxidative stress activates hepatic stellate cells, the primary drivers of fibrogenesis, accelerating disease progression. Modulating this oxidative stress offers a promising therapeutic strategy for mitigating liver damage. Klotho, an anti-aging protein, functions like a hormone to protect various organs from oxidative damage by suppressing pro-inflammatory signaling pathways and enhancing antioxidant defense mechanisms. However, reduced Klotho levels in senescent tissues impair the natural scavenging of ROS, leaving the liver vulnerable to oxidative damage and subsequent fibrotic injury. To address this deficiency, the mRNA platform offers a highly effective solution as a robust gene delivery system, capable of inducing rapid, transient and efficient protein expression in the liver without the risk of genomic integration. In this study, the potential of mRNA-mediated Klotho delivery to reduce ROS levels and inhibit the progression of liver fibrosis was investigated. To validate this approach, we treated senescence-induced hepatocytes with Klotho mRNA in vitro to assess ROS status and associated molecular markers. In addition, the mRNA was encapsulated in lipid nanoparticle (LNP) and administered to mouse model of liver fibrosis to evaluate its therapeutic efficacy in vivo. Our findings demonstrate that Klotho mRNA-based therapy serves as a novel and effective strategy for treating liver fibrosis and related hepatic injuries, offering a promising therapeutic approach for patients with hepatic diseases.
