Metabolomic and biochemical evaluation of linalool and methyl eugenol as natural alternatives to varenicline in nicotine-induced metabolic dysfunction.

N icotine, the principal addictive compound in tobacco, exerts widespread metabolic toxicity, including oxidative stress, mitochondrial dysfunction, amino acid and lipid derangements, and inflammatory damage to vital organs. Despite the clinical use of varenicline tartrate (VT) as a smoking cessation drug, its therapeutic effects on nicotine-induced metabolic dysfunction remain underexplored. Plant-derived phytochemicals such as linalool (LL) and methyl eugenol (ME), known for their antioxidant and anti-inflammatory properties, may offer comparable or superior protective effects as compared to that of VT. This study is aimed at evaluating and comparing the therapeutic efficacy of LL and ME with VT in attenuating nicotine-induced metabolic, biochemical, and histopathological abnormalities using integrated GC-MS and ESI-MS/MS-based metabolomics. Biochemical markers (ALT, AST, IL-6, TNF-α, MDA); histopathological analysis of hepatic, renal, and pulmonary tissues; and plasma metabolomic profiling using GC-MS and ESI-MS/MS were assessed in nicotine-exposed rats treated with LL, ME, and/or VT. Nicotine exposure significantly increased ROS, inflammatory cytokines, and liver enzymes while disrupting amino acid (glutamate) and lipid (LPCs, carnitines) metabolism. Histologically, nicotine caused hepatocellular vacuolation, renal tubular damage, and pulmonary congestion. Both LL and ME significantly reduced oxidative stress and inflammation, normalized glutamate levels, and restored tissue integrity. LL showed superior hepatoprotective and glutamate-restoring effects, while ME more effectively downregulated COX-2 and TNF-α. VT, although effective in reducing inflammatory markers, showed limited ability to reverse glutamate depletion or normalize lipid metabolic profiles. Unlike ME and LL, VT provided moderate histological recovery but failed to fully ameliorate tissue damage. GC-MS highlighted lipid metabolite abnormalities (e.g., LPCs, fatty acids), whereas ESI-MS/MS revealed significant reductions in oleamide and glutamate, confirming broader metabolic disruption and the superior recovery effects in LL and ME groups compared to VT. LL and ME exhibited greater therapeutic potential than VT in restoring metabolic balance and protecting against nicotine-induced organ damage. The ability of ME and LL to correct both lipid and amino acid metabolism positions them as promising natural alternatives or adjuncts for managing nicotine-associated metabolic dysfunction.