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Liver-Targeted Gallium-Polyphenol Network by Disrupting the ROS/NETs/PANoptosis Axis for Precision Acute Liver Injury
Xiaopeng Cai1, Jian He2,3, Jingwen Deng4
1Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Abstract:
Acute liver injury (ALI), driven by diverse insults such as drug toxicity and ischemia-reperfusion, poses a high mortality risk and lacks targeted therapies. While reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and a coordinated cell death pathway PANoptosis have been implicated, their interplay as a unified pathogenic axis remains elusive. Here, by integrating multi-omics analyses of clinical databases and patient samples, we systematically identified and validated the ROS/NETs/PANoptosis axis as a central driver of hepatocyte damage across multiple ALI etiologies. To therapeutically target this axis, we engineered a liver-targeted gallium-quercetin nanocomposite (Ga@Que) via coordination-driven self-assembly. Ga@Que effectively overcomes the poor bioavailability of natural quercetin. In murine models of acetaminophen-induced and ischemia-reperfusion liver injury, Ga@Que exhibited significant liver accumulation, potently scavenged ROS, suppressed neutrophil infiltration and NETs formation, and attenuated PANoptosis. Consequently, Ga@Que treatment markedly mitigated liver damage and inflammation, outperforming its individual components. Our study not only delineates a novel pathogenic paradigm in ALI but also introduces Ga@Que as a promising precision nanotherapeutic, offering a synergistic and translatable strategy to disrupt this deleterious cascade.
Insights
Researchers identified the ROS/NETs/PANoptosis axis as a key driver of acute liver injury (ALI). A novel gallium-quercetin nanocomposite (Ga@Que) effectively targeted this axis, reducing liver damage in preclinical models.
Area of Science:
- Hepatology
- Nanomedicine
- Immunology
Background:
- Acute liver injury (ALI) presents a high mortality risk with limited targeted treatments.
- The interplay between reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and PANoptosis in ALI pathogenesis is not fully understood.
- Existing therapies for ALI lack specificity and efficacy.
Purpose of the Study:
- To elucidate the ROS/NETs/PANoptosis axis as a unified pathogenic mechanism in diverse ALI etiologies.
- To develop and evaluate a novel nanotherapeutic agent targeting this axis for ALI treatment.
Main Methods:
- Multi-omics analyses of clinical databases and patient samples.
- Development of a liver-targeted gallium-quercetin nanocomposite (Ga@Que).
- In vivo evaluation of Ga@Que in murine models of acetaminophen-induced and ischemia-reperfusion liver injury.
Main Results:
- The ROS/NETs/PANoptosis axis was identified as a central driver of hepatocyte damage in ALI.
- Ga@Que demonstrated significant liver accumulation, ROS scavenging, and suppression of NETs formation and PANoptosis.
- Ga@Que treatment significantly mitigated liver damage and inflammation, outperforming individual components.
Conclusions:
- The ROS/NETs/PANoptosis axis represents a novel pathogenic paradigm in acute liver injury.
- Ga@Que is a promising precision nanotherapeutic for ALI, offering a synergistic and translatable strategy.
- Targeting this axis provides a potential new therapeutic avenue for managing acute liver injury.
