Experimental and in silico models in molecular toxicology of NAFLD: Emerging role of combination therapeutics

Non-Alcoholic Fatty Liver Disease (NAFLD) has emerged as one of the most prevalent chronic liver disorders worldwide, encompassing a pathophysiological spectrum from simple steatosis to non-alcoholic steatohepatitis, fibrosis, and cirrhosis. It is characterized by abnormal hepatic lipid accumulation, oxidative stress, mitochondrial dysfunction, and chronic low-grade inflammation. The interplay between metabolic dysregulation, such as insulin resistance and lipotoxicity, and environmental or xenobiotic factors underscores the complexity of NAFLD pathogenesis. Understanding the molecular toxicology underlying these processes has become increasingly critical, as both metabolic alterations and exposure to drugs or environmental chemicals can exacerbate hepatocellular injury and accelerate disease progression.Recent years have witnessed remarkable progress in experimental and computational models that simulate drug-induced and metabolic liver toxicity. Advanced in vitro systems incorporating primary hepatocytes, liver organoids, and co-culture models now permit detailed mechanistic studies of lipid metabolism, oxidative damage, and inflammatory signaling. Parallel developments in in silico modeling—ranging from quantitative systems toxicology and polypharmacology network analysis to artificial intelligence-driven toxicity prediction—are transforming our understanding of hepatotoxic mechanisms and facilitating early safety assessments in drug discovery.From a therapeutic perspective, integration of molecular toxicology insights has paved the way for rational combination strategies. Natural compounds such as polyphenols, flavonoids, and terpenoids demonstrate significant hepatoprotective and antioxidant potential, while receptor-targeted agents, including GLP-1 receptor agonists and FXR modulators, address key metabolic and inflammatory nodes implicated in NAFLD progression. The convergence of these modalities suggests a synergistic avenue for attenuating oxidative stress, restoring lipid homeostasis, and improving mitochondrial function.This editorial underscores the importance of merging molecular toxicology with computational and translational pharmacology to delineate the mechanisms of hepatic injury more precisely. It further advocates for the exploration of combination-based interventions that integrate natural bioactives with receptor-specific therapeutics as a next-generation strategy to combat NAFLD and related metabolic disorders.