Fenugreek Seed Powder Attenuates Lead-Induced Hepatic Injury and Renal Dysfunction in Male Mice Co-Exposed to Escalating Lead Doses

Lead (Pb) induces oxidative stress, inflammation, and hepatorenal injury. We evaluated whether fenugreek (Trigonella foenum-graecum) seed powder (200 mg/kg) protects against subchronic Pb-acetate exposure in male albino mice. Sixty mice were randomized to six groups (n = 10): control (G1), fenugreek-only (G2), Pb 150 mg/kg (G3), and three co-exposure groups receiving fenugreek with Pb at 50, 100, and 150 mg/kg (G4–G6), gavaged daily for 8 weeks. LC–DAD–ESI–MS/MS of the seed batch tentatively identified 32 metabolites, dominated by flavonoid C-glycosides, luteolin dihydrogalloyl-glucosyl-pentosyl glucoside (15.90%), vicenin-3 (14.46%), vicenin-2 (9.66%), vicenin-1 (8.80%), kaempferol 7-O-rhamnosyl-glucoside (8.71%), with additional acylated phenolic conjugates. Pb exposure (G3) significantly reduced growth and intake, elevated serum ALT, AST, ALP, urea, and creatinine, raised blood Pb, and produced hepatic necrosis, vacuolation, and inflammation. Molecularly, Pb upregulated Nrf2, HO-1, SCD-1, TNF-α, and IL-6 and suppressed SOD-3. Fenugreek co-treatment attenuated all these changes across the three Pb doses, with greatest effect at the lowest Pb load (G4). Notably, fenugreek co-treatment reduced rather than further increased Nrf2 and HO-1 expression relative to Pb alone, a pattern most consistent with lowering the upstream oxidative stimulus rather than direct induction of these pathways. The seed’s polyphenolic profile—rich in vicenin-type C-glycosides and luteolin and kaempferol derivatives—offers a plausible chemical basis for the antioxidant, anti-inflammatory, and modest Pb-lowering effects observed; however, because whole seed powder was administered and metabolite identifications are tentative, these structure–activity relationships are presented as hypotheses for future bioactivity-guided fractionation rather than as demonstrated mechanisms. These preclinical findings support further investigation of fenugreek as a candidate dietary adjunct against environmental Pb exposure, contingent on protein-level validation, pharmacokinetic characterization, benchmarking against a standard chelator, and bioactivity-guided fractionation.