Mo₂C nanozyme targets citrate synthase to treat acute kidney injury through alleviating oxidative stress and dysfunction of energy metabolism.

Abstract

Acute kidney injury (AKI), characterized by rapid renal dysfunction, lacks effective therapies due to its complex pathophysiology involving oxidative stress and mitochondrial damage. Molybdenum carbide (Mo₂C) nanozymes show promise through their tunable catalytic properties and reactive oxygen species (ROS)-scavenging capacity. To elucidate the metabolic basis of their therapeutic effects, we employed metabolomics analysis for molecular-level metabolic profiling, combined with evaluation in lipopolysaccharide (LPS)-, cisplatin (CP)-, and ischemia-reperfusion injury (IRI)-induced AKI models and TCMK-1 cell validation. Key findings demonstrated that Mo₂C restored renal function, reduced oxidative damage/apoptosis, and preserved mitochondrial integrity. Metabolomic mechanistic investigation revealed normalization of dysregulated pathways including glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. Consistently, in LPS-challenged TCMK-1 cells, Mo₂C suppressed ROS, attenuated apoptosis, reduced inflammation, and specifically stabilized TCA cycle function. Most importantly, inhibition of citrate synthase causally demonstrated that Mo₂C's renoprotection depends on TCA cycle modulation. These integrated findings establish Mo₂C nanozymes as a novel AKI treatment paradigm through TCA cycle homeostasis restoration, with significant translational potential. To realize this potential, future studies focusing on comprehensive safety profiling and clinical validation may facilitate the translation of Mo₂C nanozymes into therapeutic applications for AKI and related renal disorders.