From Environmental Fate to Toxicological Mechanisms: Unveiling the Hidden Risks of Ginkgolic Acids as Emerging Natural Contaminants

Ginkgolic acids (GAs), a class of natural alkylphenolic compounds prevalent in Ginkgo biloba-derived products widely used across industries, have emerged as persistent environmental micropollutants with documented multiorgan toxicity (genotoxicity, neurotoxicity, allergenicity, hepatotoxicity). Critically, inconsistent regulatory standards and inadequate monitoring for GAs in consumer products and industrial waste streams lead to unrecognized environmental release and potential human exposure. However, the congener-specific environmental risks and underlying mechanisms of GA-induced toxicity, particularly to major detoxification organs, remain poorly characterized, hindering evidence-based risk assessment and management. This study establishes the first congener-resolved toxicological framework for GAs, directly linking chemical structure to environmental fate, bioactivity, and multiorgan toxicity using an integrated strategy combining network toxicology, deep learning, molecular docking, and experimental validation. Network analysis identified 52 hepatotoxicity- and 21 nephrotoxicity-related targets. Crucially, it identifies GA C17:2 as a high-priority environmental toxicant, showing strong binding affinity and stable interactions with 10 core toxicity-related proteins. GA C17:2 showed acute cytotoxicity (IC50: 24.2 nM in Hep G2; 195 nM in HK-2), induced dose-dependent hepatorenal damage in vivo via PPARA degradation, lipid disorder, ACSL4-mediated ferroptosis, inflammation, and apoptosis, with shared PPAR signaling, ferroptosis, and fatty acid degradation pathways. The framework provides a powerful, mechanism-driven strategy for environmental risk prioritization of emerging contaminants like GAs. Our findings deliver critical scientific evidence to support the urgent development and harmonization of regulatory standards for GAs monitoring in environmental matrices and waste streams, ultimately mitigating ecosystem burdens and protecting human health from this under-regulated contaminant class.