Atomically Precise Pt ₃ Cu ₂ Clusters Restore Energy Metabolism via Targeted Succinate Degradation

Abstract

ABSTRACT Succinate is a critical intermediate for the tricarboxylic acid cycle, whose abnormal accumulation can disrupt energy homeostasis and trigger systemic inflammatory injury across dominant metabolic organs. Targeting succinate thus represents a pivotal strategy to reestablish metabolic equilibrium. Here, through biomimetic electronic structure engineering, we report an atomically precise Pt 3 Cu 2 cluster engineered with intrinsic succinate dehydrogenase (SDH)‐mimicking activity that catalyzes succinate oxidation to restore energy metabolism. The Pt 3 Cu 2 cluster exhibits a succinate‐binding affinity 4.52‐fold superior to that of native SDH, wherein the Pt─Cu dual‐metal active center structurally and functionally recapitulates the Fe─S catalytic motifs of SDH, enabling precise substrate recognition and efficient electron transfer. In disease models of energy metabolic dysfunction, Pt 3 Cu 2 reduces succinate accumulation by 43.54% and restores ATP production by 5.31‐fold, effectively rescuing hepatic energy metabolic dysfunction. Concurrently, it decreases lipid accumulation by 79.82% and resolves hepatic inflammation through normalization of the PI3K/Akt signaling axis. Beyond the liver, systemic normalization of succinate and inflammatory cytokines attenuates neuroinflammation, restores cerebral energy supply, and improves cognitive function. This work establishes atomically precise metal nanoclusters as a compelling enzyme‐mimetic strategy for targeting metabolic‐inflammatory diseases.