Decoding Precursor Pharmacophore Retention in Nanozymes for Synergistic Catalytic‐Immunomodulatory Protection Against Acute Liver Injury

ABSTRACT Acute liver injury (ALI) is driven by concurrent dysregulation of oxidative stress and endogenous defense signaling, yet current nanozyme‐based approaches predominantly act as passive scavengers of reactive oxygen species (ROS) with limited biological specificity. Herein, we report a precursor‐programmed strategy to construct single‐atom nanozymes with defined pharmacophore inheritance, enabling the integration of catalytic and signaling functionalities within a single carbon dot. By employing histidine, Mn, and silibinin (SLB) as precursors, HS‐Mn‐CDs featuring atomically dispersed Mn‐N 4 active centers are synthesized, exhibiting efficient superoxide dismutase (SOD)/catalase (CAT)‐mimicking activity for ROS cascade elimination. More importantly, by integrating structural characterization, molecular docking simulations, network pharmacology analysis, and, SPR analysis we provide complementary evidence indicating that SLB‐derived pharmacophore fragments are structurally preserved on the carbon framework, while HS‐Mn‐CDs interact with Nrf2, supporting activation of the Nrf2/ARE endogenous antioxidant defense pathway. This dual mechanism establishes a synergistic paradigm that couples exogenous catalytic detoxification with pharmacophore‐mediated biological regulation, significantly improving the immune microenvironment of damaged livers, thereby enabling the effective protection against ALI. Beyond its hepatoprotective efficacy, this study directs mechanistic insight into precursor‐derived structure‐activity inheritance, offering a generalizable strategy for designing next‐generation nanozymes with programmable biological functions.