Guazuma ulmifolia butanol extract protects against cadmium-induced hepatotoxicity via HO-1/Sirt-1 activation, miRNA-lncRNA modulation, and metabolic reprogramming.

BACKGROUND

Guazuma ulmifolia is traditionally used for liver disorders, but its protective mechanisms against heavy metal toxicity are poorly defined. This study evaluated the phytochemical profile and hepatoprotective mechanisms of G. ulmifolia butanol extract (Gul-BuOH) against cadmium-induced liver injury.

METHODS AND FINDINGS: Gul-BuOH was chemically profiled by UPLC-PDA-ESI-qTOF-MS/MS. Cadmium hepatotoxicity was induced in rats, followed by Gul-BuOH treatment (100 and 200 mg/kg). Liver injury, oxidative stress, inflammation, gene expression (Let-7a, HOTAIR), histopathology, HO-1/Sirt-1 immunoreactivity, and serum metabolomic changes were assessed. Chemical profiling led to the annotation of 42 compounds, including mainly flavonoids and phenolic acids, highlighting the rich phytochemical composition of G. ulmifolia. CdCl2 exposure increased hepatic Cd accumulation and elevated ALT, AST, and ALP, reduced TAC, and increased NO and MDA. Gul-BuOH significantly reduced hepatic Cd levels by 2.6- and 3.2-fold, restored TAC by 38.3% and 83.2%, and decreased NO (56.3% and 63.4%) and MDA (45.4% and 54.6%) at 100 and 200 mg/kg, respectively. Inflammatory markers NF-κB-p and TNF-α were markedly suppressed, while miRNA Let-7a was upregulated and lncRNA HOTAIR was downregulated. Histological and immunohistochemical analyses revealed near-complete restoration of hepatic architecture and normalization of HO-1 and Sirt-1 expression at the high dose. Serum metabolomics' OPLS-DA model performance indicators demonstrated strong reliability, with an R2Y (explained variance) of 0.991 and a Q2 (predictive variance) of 0.988). The model identified 36 significantly altered metabolites that were largely normalized by Gul-BuOH, implicating linoleic acid metabolism, amino acid biosynthesis, and ascorbate-related pathways.

CONCLUSION

Gul-BuOH affords dose-dependent protection against Cd-induced liver injury by modulating oxidative stress, inflammation, metal detoxification, and metabolic pathways, supporting the traditional use of G. ulmifolia and its potential as a multi-target hepatoprotective agent.