{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:10:31Z","timestamp":1784182231009,"version":"3.55.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Although cullin-family E3 ubiquitin ligases regulate diverse oncogenic pathways, the role of\n                      <jats:italic>CACUL1<\/jats:italic>\n                      in hepatocellular carcinoma (HCC) remains poorly characterized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed pan-cancer expression and survival analysis using TCGA and GEO databases, validated findings through immunohistochemistry, and conducted functional studies in HCC cell lines using CRISPR-mediated\n                      <jats:italic>CACUL1<\/jats:italic>\n                      knockout. Transcriptome sequencing, functional assays (CCK-8, wound-healing, transwell invasion), and single-cell RNA-sequencing were performed to elucidate mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pan-cancer analysis identified\n                      <jats:italic>CACUL1<\/jats:italic>\n                      overexpression in HCC and gastric cancer (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.001), with prognostic significance in 16 tumor types, including HCC (log-rank\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01).\n                      <jats:italic>CACUL1<\/jats:italic>\n                      expression independently predicted poor HCC prognosis (multivariable Cox,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05) and correlated with advanced clinicopathological features and reduced immune checkpoint expression.\n                      <jats:italic>CACUL1<\/jats:italic>\n                      knockout inhibited HCC cell proliferation and migration but not invasion, with transcriptomic analysis revealing PI3K\/AKT signaling pathway enrichment. Co-culture experiments demonstrated that\n                      <jats:italic>CACUL1<\/jats:italic>\n                      promotes M2 macrophage polarization through Notch1 suppression, with pharmacological Notch inhibition phenocopying this effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CACUL1<\/jats:italic>\n                      functions as a dual-axis oncogenic driver in HCC through enhanced tumor cell proliferation associated with PI3K\/AKT signaling and immune evasion via Notch1-dependent macrophage polarization, positioning it as a candidate prognostic biomarker and therapeutic target.\n                    <\/jats:p>\n                  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