{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:36:22Z","timestamp":1790314582812,"version":"4.1.0"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"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>Hepatocellular carcinoma ranks among the most prevalent malignancies worldwide. While stress can modulate tumor initiation, progression, metastasis, and therapeutic response through diverse mechanisms, its specific role in hepatocellular carcinoma pathobiology remains elusive. This study aimed to elucidate the role of the gut microbiota in stress-promoted hepatocellular carcinoma progression and to uncover the pathways associated with disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Integrating clinical and preclinical models, we delineated stress-induced restructuring of the gut microbiota and functionally restored specific microbial constituents. Mechanistic insights into the microbial metabolite indole-3-propionic acid were derived through\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      interrogations of the hepatocellular carcinoma tumor microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Stress profoundly remodels the gut microbiota, with\n                      <jats:italic>Phocaeicola vulgatus<\/jats:italic>\n                      being significantly reduced. Restoration of\n                      <jats:italic>Phocaeicola vulgatus<\/jats:italic>\n                      or administration of its tryptophan-derived metabolite indole-3-propionic acid significantly attenuated hepatocellular carcinoma progression\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Indole-3-propionic acid treatment reduced endothelial JAM2 expression and was associated with reduced JAM2\u2013F11R-mediated endothelial\u2013macrophage crosstalk in hepatocellular carcinoma, which may contribute to suppression of tumor progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support a role for the stress\u2013gut microbiota\u2013metabolite\u2013tumor microenvironment axis in hepatocellular carcinoma progression and suggest potential translational targets for microbiome-based therapeutic strategies.<\/jats:p>\n                  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