{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:20:56Z","timestamp":1792167656855,"version":"4.4.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The nuclear receptor\n                    <jats:italic>Nurr1<\/jats:italic>\n                    (NR4A2) is a transcriptional regulator of inflammatory homeostasis, but its systemic effects on orchestrating inter-organ communications are largely unknown. Here we show that\n                    <jats:italic>Nurr1<\/jats:italic>\n                    haplo-insufficiency results in a lethal coupled disorder across the liver-gut axis. Using a CRISPR-Cas9 generated murine model, we find that metabolically-activated heterozygous deficiency of\n                    <jats:italic>Nurr1<\/jats:italic>\n                    results in profound hepatocellular necrosis and marked hepatic activation of inflammatory and pro-fibrotic genes coupled with dysregulation of the intestinal barrier, and severe small-intestinal dysbiosis. Multi-omics integration reveals a highly penetrant transcriptional signature of this herein termed liver-gut disorder, achieving up to 0.950 accuracy (SVM-RBF, 10-fold cross-validation) in classifying genotypes from integrated multi-omics features. Notably, we also demonstrate that these gene level perturbations in\n                    <jats:italic>Nurr1<\/jats:italic>\n                    haplo-insufficiency can be thought of as learnable tissue \u2018morphologies\u2019 detectable by AI. Next, we created deep convolutional neural networks that accurately classify genotype from routine histopathology. Our algorithm achieves 99.50% accuracy in classifying hepatic fibrosis (Sirius Red), 99.20% in liver inflammation (H&amp;amp;E) and 92.31% in intestine (H&amp;amp;E). We provide the first multi-omics phenotype of\n                    <jats:italic>Nurr1<\/jats:italic>\n                    deficiency, revealing its pivotal regulatory role in coordinating liver-gut homeostasis, and establishing a histopathological AI-driven framework. Grad-CAM saliency analysis confirms biological interpretability. Translational relevance is supported by human transcriptomic data (E-GEOD-61260) showing concordant upregulation of\n                    <jats:italic>COL1A1<\/jats:italic>\n                    (log\n                    <jats:sub>2<\/jats:sub>\n                    FC= + 0.725,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt;\u00a00.01),\n                    <jats:italic>TGFB1<\/jats:italic>\n                    (+ 0.429,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt;\u00a00.05), and\n                    <jats:italic>MMP9<\/jats:italic>\n                    (+ 0.969,\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&amp;lt;\u00a00.01) alongside reduced NR4A2\/\n                    <jats:italic>NURR1<\/jats:italic>\n                    in human liver disease.\n                  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International University","place":["Islamabad, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piniel Alphayo","family":"Kambey","sequence":"additional","affiliation":[{"name":"Medical Research Institute, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul","family":"Malik","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]},{"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]},{"name":"China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Adeel","family":"Ejaz","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]},{"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajjad Ali","family":"Shah","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology and Microbiology, Bacha Khan University","place":["Charsadda, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-Xiong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of 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