AniView Supports Acute Liver Failure Research: Pathogenic Ifit1+ neutrophils driven by IRF7 promote liver injury and represent a therapeutic target in acute liver failure

IRF7-driven pathogenic Ifit1⁺ neutrophils promote liver injury and represent a potential therapeutic target in acute liver failure.

Researchers Xianbo Wang and Ying Feng from Beijing Ditan Hospital, Capital Medical University, together with Liying Li’ s team, have made new progress in the fields of hepatology and immunology. Their findings were published in " HEPATOLOGY" (IF = 18.0, a top journal in the Chinese Academy of Sciences Q1 category) under the title "Pathogenic Ifit1⁺ neutrophils driven by IRF7 promote liver injury and represent a therapeutic target in acute liver failure."

This study provides new insights into the identification of pathogenic Ifit1⁺ neutrophil subsets driven by IRF7 and highlights their potential as precise therapeutic targets for acute liver failure intervention.

Acute liver failure (ALF) is a life-threatening disease with high mortality and extremely limited clinical treatment options. During acute liver injury, neutrophils, acting as the "first responders" of immune defense, rapidly and massively infiltrate the damaged liver. However, neutrophils have traditionally been regarded as a homogeneous cell population, overlooking their complex phenotypic and functional heterogeneity. Whether neutrophils aggravate inflammatory storms or promote tissue repair during ALF progression, as well as their specific cellular subtypes, functional evolution characteristics, and upstream regulatory mechanisms, remain largely unclear, greatly limiting the development of neutrophil-targeted therapies for ALF. In this study, researchers first used single-cell RNA sequencing (scRNA-seq) to systematically analyze neutrophil heterogeneity during ALF progression and successfully identified an IRF7-driven pathogenic Ifit1⁺ neutrophil subset, providing a novel target for precise ALF intervention.

However, the precise delivery of therapeutic agents targeting this subset, such as the IRF7 inhibitor HS38, to the lesion site remains a critical challenge for clinical translation. Conventional systemic administration often results in nonspecific drug distribution in non-target organs, including the spleen, lungs, and kidneys, which not only reduces the local therapeutic concentration in the liver but may also cause severe systemic toxicity. To address this challenge, the research team developed a novel targeted nanoparticle system (AcLNP-HS38).

Research team developed a lipid nanoparticle (LNP)-based delivery system to selectively target hepatic neutrophils. LNPs were selected as the delivery platform owing to their inherent liver tropism.To further enhance neutrophil specificity, we functionalized the LNPs with the neutrophil-targeting peptide Ac-PGP, which selectively binds to the CXCR2 receptor on the neutrophil surface.1Accordingly, we constructed an Ac-PGP–modified LNP formulation (AcLNP) loaded with HS38 (AcLNP-HS38) for targeted inhibition of hepatic neutrophil IRF7.

Experiments using AniView

To directly and quantitatively evaluate whether these nanoparticles could specifically accumulate in acutely injured liver tissue and avoid uptake by non-target organs under complex in vivo conditions, the researchers used the AniView multimodal animal in vivo imaging system from Guangzhou Biolight Biotechnology to visualize and quantitatively analyze the organ-targeting capability of the nanoparticles.

To minimize interference from autofluorescence of mouse tissues and improve imaging penetration depth, researchers encapsulated and covalently labeled the nanoparticles with the near-infrared fluorescent dye Cy5. Mice were first treated with D-GalN/LPS (D/L) to establish an ALF model. Thirty minutes later, four formulations were administered via tail vein injection: PBS (control group), free fluorescent nucleic acid (siR-Cy5), conventional nanoparticle-encapsulated nucleic acid (LNP-siR-Cy5), and targeted nanoparticle-encapsulated nucleic acid (AcLNP-siR-Cy5).

Whole-body fluorescence imaging was performed 1 hour after injection to quantify fluorescence signal accumulation in the liver region. Subsequently, mice were sacrificed, and major organs, including the liver, heart, spleen, lungs, and kidneys, were collected for ex vivo fluorescence imaging to quantitatively analyze nanoparticle biodistribution.

In vivo imaging results demonstrated that, compared with the control groups, mice injected with AcLNP-siR-Cy5 exhibited significant accumulation of Cy5 fluorescence signals in the liver region. Ex vivo organ imaging and quantitative analysis further confirmed that the nanoparticles were predominantly enriched in severely injured liver tissue, while nonspecific accumulation in organs such as the heart, lungs, and kidneys was minimal, indicating the excellent liver lesion-targeting capability of this nanoparticle system.

DOI: org/10.1097/HEP.0000000000001738