{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:57Z","timestamp":1792787637993,"version":"4.5.0"},"reference-count":37,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":56,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["R37 AA020518"],"award-info":[{"award-number":["R37 AA020518"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["R21 AA030617"],"award-info":[{"award-number":["R21 AA030617"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["R01AA031230"],"award-info":[{"award-number":["R01AA031230"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01 DK124612"],"award-info":[{"award-number":["R01 DK124612"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01 DK106540"],"award-info":[{"award-number":["R01 DK106540"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01 DK134737"],"award-info":[{"award-number":["R01 DK134737"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>\n                    Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring tuberous sclerosis complex 1 (\n                    <jats:italic>TSC1<\/jats:italic>\n                    ) mutations exhibits more aggressive behavior. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific\n                    <jats:italic>Tsc1<\/jats:italic>\n                    -knockout (L-\n                    <jats:italic>Tsc1<\/jats:italic>\n                    \u2013KO) and L-\n                    <jats:italic>Tsc1<\/jats:italic>\n                    <jats:italic>Tfeb<\/jats:italic>\n                    \u2013double KO mice. Loss of hepatic\n                    <jats:italic>Tsc1<\/jats:italic>\n                    led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-\n                    <jats:italic>Tsc1<\/jats:italic>\n                    \u2013KO mice showed increased hepatocyte plasticity, decreased HNF4\u03b1, increased YAP activation, and spontaneous HCC with increased SOX9- and CK19-positive biliary epithelial cell\u2013like cells at 8\u201312 months. Deletion of\n                    <jats:italic>Tfeb<\/jats:italic>\n                    dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-\n                    <jats:italic>Tsc1<\/jats:italic>\n                    \u2013KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to noncanonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC.\n                  <\/jats:p>","DOI":"10.1172\/jci206334","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T16:00:26Z","timestamp":1786032026000},"source":"Crossref","is-referenced-by-count":0,"title":["Noncanonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma"],"prefix":"10.1172","volume":"136","author":[{"given":"Chen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojuan","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and 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