Mo₂C Nanozyme Targets Citrate Synthase to Treat Acute Kidney Injury through Alleviating Oxidative Stress and Dysfunction of Energy Metabolism

Two mouse models of AKI—specifically lipopolysaccharide (LPS)- and cisplatin (CP)-induced AKI—were established to evaluate the therapeutic effects of molybdenum carbide (Mo₂C) nanozymes. Comprehensive metabolomic profiling was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect alterations in metabolites and metabolic pathways in the mice. The therapeutic efficacy of Mo₂C nanozymes was further validated in TCMK-1 renal epithelial cells, with assessments including cell viability, oxidative stress levels, and apoptotic activity. To investigate the mechanism underlying the renoprotective effect of Mo₂C nanozymes, citrate synthase was inhibited, and subsequent changes in the nanozymes’ renoprotective activity were monitored (Figure 1).

Treatment with Mo₂C nanozymes effectively restored renal function in both lipopolysaccharide-induced and cisplatin-induced AKI mouse models, significantly attenuating oxidative damage and cellular apoptosis while preserving mitochondrial integrity (Figure 2-3). Additionally, Mo₂C nanozymes reversed dysregulated energy metabolism pathways in AKI mice (including glycolysis, tricarboxylic acid cycle, pentose phosphate pathway, amino acid metabolism, oxidative phosphorylation, and urea cycle) to reestablish metabolic homeostasis. In lipopolysaccharide-stimulated TCMK-1 cells, Mo₂C nanozymes inhibited ROS generation, reduced apoptosis, decreased inflammatory mediator levels, maintained mitochondrial membrane potential stability, and improved tricarboxylic acid cycle disturbance. Notably, the renoprotective effect of Mo₂C nanozymes was significantly diminished in lipopolysaccharide-stimulated TCMK-1 cells after citrate synthase inhibition (Figure 4).

Mo₂C nanozymes exhibit strong therapeutic effects in both LPS- and CP-induced AKI models. By scavenging ROS, reducing oxidative damage and apoptosis, preserving mitochondrial function, and reactivating the tricarboxylic acid (TCA) cycle—specifically via restoring citrate synthase activity and key TCA metabolites (citrate, malate, fumarate, succinate)—they normalize energy metabolism, as confirmed in both in vitro and in vivo studies. These results confirm that Mo₂C nanozymes treat AKI by restoring TCA cycle homeostasis, thereby offering a novel therapeutic paradigm for oxidative stress-mediated renal diseases with translational potential (Figure 5). Future studies should focus on the safety profiling and clinical validation of Mo₂C nanozymes to advance their application in the treatment of AKI and related renal disorders.