Dietary Supplementation of Lotus (Nelumbo nucifera Gaertn.) Extract Alleviates Liver Injury Induced by 2-Methoxyethanol in Mice Model

2-Methoxyethanol (2-ME), a phthalic acid ester widely used in the plastics industry, can cause liver injury. Natural plant substances with antioxidant properties are promising candidates for alleviating such injury. While hepatoprotective effects of Nelumbo nucifera seeds and leaves have been documented, the potential of N. nucifera flower extract against 2-ME-induced hepatotoxicity remains unexplored. This study investigated the hepatoprotective effects of N. nucifera flower extract on male Balb/C mice exposed to 2-ME and identified its secondary compounds. The study design included five groups: normal control (CN) group, positive control (CP) group receiving 2-ME only for 7 days, and treatment groups receiving 2-ME for 7 days followed by N. nucifera flower extract at 50 (low), 150 (moderate), and 450 (high) mg/kg body weight (bw) for 28 days. Liver histology and biochemistry parameters results revealed that the N. nucifera flower extract significantly (p < 0.05) mitigated hepatocyte damage caused by 2-ME by decreasing the levels of liver enzyme (AST, ALT, and ALP), oxidative stress (MDA), and cytokine pro inflammatory (IL-6 and TNF-α). The middle and high dose provided good protection for liver injury against 2-ME. Spearman correlation analysis showed strong positive correlations between MDA, IL-6, TNF-α levels and liver histopathological scores (r > 0.8; p < 0.05), suggesting that the reduction in oxidative and inflammatory markers is closely associated with decreased hepatocellular damage. These protective effects are attributed to the antioxidant activity (IC50 = 63.42 ppm) and active compounds in N. nucifera flower extract, which include cycloartenol acetate, hexadecanoic acid, 6beta-bicyclo(4.3.0)nonane, delta-guaiene, 24-norursa-3,12-diene, campesterol, lupeol, stearic acid, gamma-sitostenone, and 3-methylphenol. In silico analysis showed that 24-norursa-3,12-diene has a high binding afinity (-8.2 kcal/mol) with prekursor of cytokine proinflammatory (NF-κB). Further studies are recommended to confirm the optimal dosage and elucidate the underlying mechanisms.