Berberine Attenuates Cadmium-Induced Nephrotoxicity by Suppressing LDHA-Mediated Glycolytic Reprogramming and Restoring Mitochondrial TCA Cycle Metabolism

Cadmium (Cd) is an environmental nephrotoxicant that preferentially accumulates in the kidney and disrupts redox and energy metabolism. However, the protective effect of berberine (Ber) against Cd-induced nephrotoxicity remains insufficiently characterized. In the present study, male C57BL/6 mice were orally exposed to CdSO4 (30 mg/kg body weight/day) for 30 days in the absence or presence of berberine (25 or 100 mg/kg/day). Renal function, histopathology, oxidative stress parameters, LC–MS/MS-based metabolomic profiling, gene and protein expression, and in silico ligand–target interactions were evaluated. Cd exposure markedly increased serum CREA, renal index, renal LDH activity, and MDA content, decreased SOD and CAT activities, and induced pronounced renal histopathological lesions. Ber significantly attenuated these abnormalities in a dose-dependent manner. Metabolomic analysis revealed that Cd broadly suppressed pyruvate metabolism, tricarboxylic acid cycle intermediates, and NAD+/NADH homeostasis, whereas berberine restored the levels of pyruvate, acetyl-CoA, oxaloacetate, citrate, isocitrate, succinate, fumarate, malate, NAD+, and NADH. In parallel, berberine normalized the expression of metabolism-related genes including the downregulation of Ldha and the upregulation of Cs, Sucnr1, G6pc, and Pfkm, with the high-dose regimen showing the most evident recovery. Western blotting further verified the lower LDHA protein expression after berberine treatment. Molecular docking demonstrated favorable potential berberine–LDHA binding, and molecular dynamics simulation supported the stability of the ligand–protein complex. Collectively, these findings indicate that berberine ameliorates Cd-induced renal injury, an effect that correlates with attenuated oxidative stress, modulation of LDHA-associated glycolytic pathways, and restoration of mitochondrial TCA-cycle activity and redox balance, highlighting berberine as a promising candidate for the prevention of heavy metal-associated nephrotoxicity.