Abstract

Stress-mediated hepatotoxicity-liver injury driven or amplified by oxidative stress, endoplasmic reticulum (ER) 
stress, mitochondrial dysfunction, and inflammation-represents a convergent pathway for a broad range of chemical, 
biological and metabolic insults. Contributors include xenobiotics (drugs, environmental toxins), ischemia
reperfusion, viral infections, metabolic overload (nonalcoholic fatty liver disease), and lifestyle factors. The 
pathophysiology is characterized by redox imbalance, reactive oxygen and nitrogen species (ROS/RNS) formation, 
unfolded protein responses, impaired bioenergetics, and activation of innate immune signaling culminating in 
hepatocellular death (apoptosis, necrosis, necroptosis) and fibrogenic remodeling. Phytomedicines plant-derived 
extracts and purified phytochemicals offer multiple, often pleiotropic mechanisms for hepatoprotection: direct 
antioxidant activity, induction of endogenous cytoprotective pathways (Nrf2/ARE), attenuation of ER stress, 
preservation of mitochondrial function, anti-inflammatory effects (NF-κB, inflammasome modulation), and 
inhibition of profibrogenic signaling. This review synthesizes mechanistic insights from preclinical models and the 
highest-quality clinical evidence to date, highlights leading phytochemical candidates (e.g., silymarin, curcumin, 
resveratrol, berberine, green tea catechins, quercetin, glycyrrhizin), discusses formulation and safety challenges, and 
proposes a research agenda to translate phytomedicines into evidence-based hepatoprotective interventions. We 
argue that, with standardized extracts, rigorous pharmacokinetic characterization and integrated safety monitoring, 
phytomedicines can complement conventional strategies to prevent or mitigate stress-mediated liver injury across 
clinical settings.