ArticleBMC pharmacology & toxicology2025
Exploring the toxic mechanism of excessive intake of naringin on drug-induced liver injury using network toxicology and experiment validation strategy.
Article in BMC pharmacology & toxicology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundExcessive intake of citrus fruits may affect liver metabolism and trigger various adverse reactions. Naringin, a natural flavonoid compound, is mainly extracted from the citrus fruits. Previous studies have reported that naringin poses the protective effects of hepatotoxicity. However, it is currently unclear whether high-dose intake of naringin causes liver toxicity. This study aims to rigorously evaluate the toxicity of excessive intake of naringin for drug-induced liver injury (DILI) utilizing network toxicology and molecular docking methodologies.
methodswe conducted a systematic investigation into the toxicity and underlying molecular mechanisms associated with high-dose intake of naringin-induced DILI by utilizing various bioinformatics approaches including drug toxicity analysis, PPI protein network analysis, GO and KEGG enrichment analysis, molecular docking simulation and in vitro experiment validation.
resultsOur findings indicated that naringin posed a significant risk in inducing DILI. The results observed that when the concentration of naringin reached 400µM, it inhibited the viability of HepaRG cells, boosted AST and ALT activity, and increased the levels of inflammatory factors TNF-α and IL-1β. Based on PPI network analysis, we identified six hub genes, including CASP3, PPARG, PTGS2, PARP1, HSP90AA1, and ESR1. KEGG enrichment analysis had screened out several crucial pathways. Molecular docking results showed that naringin might have strong binding ability to six proteins. We verified four key proteins for naringin induced DILI via the cross analysis between DILI datasets GSE54255 and GSE74000 and the naringin related targets. Finally, the mRNA expression level of the four genes was detected and found that when the concentration of naringin reached 400 µM, the expression level of HSP90AA1, CASP3, and PTGS2 significantly was upregulated while the PARP1 expression was decreased in HepaRG cells.
conclusionThe study found that high dose naringin could induce DILI in vitro experiment, and its potential mechanisms were explored through network toxicology and molecular docking strategies. This research provides a theoretical framework for understanding the underlying molecular mechanisms of high-dose intake of naringin-induced DILI. CLINICAL TRIAL NUMBER: Not applicable.
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