Targeting ferroptosis as a therapeutic strategy for hepatotoxicity
Negar Hemmati, Mahdieh Anoush, Bahman Abedi Kiasari, Alireza Torkamani
Abstract
Hepatotoxicity is a global health problem with a scarcity of treatment modalities that can reverse extensive liver injury. The liver's central role in detoxification, iron regulation, and redox balance makes it highly vulnerable to toxic, metabolic, and inflammatory insults. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key mechanism linking oxidative stress, disrupted iron homeostasis, and hepatocellular injury Ferroptosis differs from apoptosis or necroptosis since it entails metabolic frailties of the glutathione-GPX4 system, the FSP1-CoQ10 system, and the BH4/DHFR system with peroxidation failure-prone lipid remodeling processes. Notably, growing evidence implicate ferroptosis in a number of hepatic disorders, including drug-induced liver injury, alcoholic and non-alcoholic liver disease, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. Beyond acute death of hepatocytes, chronic ferroptotic signaling also enhances fibrogenesis and accelerates cirrhosis and hepatocellular carcinoma, and viral hepatitis exploits ferroptotic mechanisms via iron imbalances and oxidative stress. Acting both sides of this coin, pathogenic catalyst of parenchymal disease and therapeutic target of malignancy, puts ferroptosis both as a liability and a target. New therapeutic modalities, including natural products, synthetic small molecules, mesenchymal stem cell derivatives, and nanoparticle systems, modulate ferroptotic signaling to enhance antioxidant defenses, restore iron balance, or selectively induce tumor cell death. Collectively, these strategies underscore the translational promise of ferroptosis-based interventions. This review integrates mechanistic insights with emerging therapies, positioning ferroptosis as a context-dependent driver of hepatotoxicity and a compelling target for precision liver medicine.