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Scheme 1. The pathological mechanisms underlying APAP-induced DILI and the therapeutic efficacy of RNPs. When APAP exceeds the therapeutic dose, it is metabolized to generate highly active NAPQI, which forms toxic protein adducts that disrupt the normal structure and function of cells, trigger oxidative stress and inflammatory responses, and ultimately lead to liver damage. In a mouse model of APAP-induced DILI, tail vein injection of RNPs reverses liver cell damage and restores liver structure and function by inhibiting RONS and inflammatory signals. [Display omitted] With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun- N -terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N -acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function. [ABSTRACT FROM AUTHOR]

Highlights: [•] VPO1 was over-expressed in hypertensive SHRs as compared to WKY rats. [•] VPO1 over-expression was accompanied by increased oxidative stress. [•] VPO1 over-expression was found to be related to impaired endothelial function. [ABSTRACT FROM AUTHOR]