Speakers
Description
Drug-induced liver injury (DILI) is a leading cause of acute liver failure with limited therapeutic options. Cytochrome P450 2E1 (CYP2E1) plays a critical role in DILI pathogenesis by catalyzing the bioactivation of hepatotoxic drugs into reactive intermediates and generating oxidative stress, creating a self-perpetuating injury cycle. However, clinical translation of CYP2E1 inhibitors has been hindered by insufficient potency, poor selectivity, and off-target toxicity. Here we report the discovery and characterization of Api-4, a novel flavonoid-based CYP2E1 inhibitor developed through high-throughput screening and structure-activity relationship optimization. Api-4 exhibits exceptional potency against CYP2E1 with an IC50 value of 1.4 μM and demonstrates remarkable isoform selectivity over other cytochrome P450 enzymes. In acetaminophen (APAP) and thioacetamide(TAA)-induced liver injury, Api-4 significantly attenuated liver injury by suppressing CYP2E1-mediated reactive metabolite formation, preserving intracellular glutathione levels, and disrupting the positive feedback loop of oxidative stress-driven CYP2E1 upregulation. Additionally, mechanistic investigations revealed that Api-4 modulates endogenous lipid metabolism, leading to the accumulation of specific lipid species that serve as endogenous ligands for peroxisome proliferator-activated receptor alpha (PPARα). This indirect PPARα activation contributes to enhanced fatty acid oxidation and anti-inflammatory responses, further amplifying its hepatoprotective effects. Thus, Api-4 exerts dual hepatoprotective mechanisms through direct CYP2E1 inhibition and indirect PPARα agonism via metabolic remodeling. These findings establish Api-4 as a highly potent and selective first-in-class CYP2E1 inhibitor with promising therapeutic potential for DILI intervention, addressing a critical unmet need in clinical hepatology.
