{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:23:23Z","timestamp":1787311403445,"version":"build-2736575974"},"reference-count":69,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:00:00Z","timestamp":1767398400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473395"],"award-info":[{"award-number":["82473395"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018904","name":"Beijing Xisike Clinical Oncology Research Foundation","doi-asserted-by":"publisher","award":["Y\u2010Gilead2024\u2010PT\u20100006"],"award-info":[{"award-number":["Y\u2010Gilead2024\u2010PT\u20100006"]}],"id":[{"id":"10.13039\/100018904","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>TROP2, a critical cell surface oncogenic signal transducer, is increasingly linked to refractory metastatic colorectal cancer (CRC) and other solid tumours. Robust lactate accumulation within metastatic niches correlates with pathological metastatic progression. Anti\u2010TROP2 antibody\u2010drug conjugates (ADCs) are clinically available but show limited efficacy in advanced metastatic CRC. Elucidating how TROP2 signalling orchestrates molecular and cellular programs enabling CRC metastatic progression would help improve metastasis therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Tissue microarray, immunohistochemistry, and western blotting delineated TROP2's pathological role in CRC liver metastasis (CRLM). Metabolomics characterised TROP2\u2010mediated metabolic effect. Western blot detected TROP2 responsive lactylation sites. Cell\u2010derived xenograft (CDX), intra\u2010splenic injection models, and patient\u2010derived xenografts (PDX) validated TROP2 or TROP2\u2010induced H3K18 lactylation (H3K18la) in CRLM pathogenesis and Acriflavine therapeutic response. Genome\u2010wide H3K18la profiling was performed by ChIP\u2010seq.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we identify a self\u2010reinforcing positive feedback loop between H3K18la and TROP2 in CRC cells that drives CRC metastatic progression. We show that TROP2 is elevated during CRC metastatic process, with high TROP2 levels in liver metastases predicting increased post\u2010therapy recurrence in two distinct cohorts. We find that H3K18la levels are upregulated in CRC cells in response to TROP2 expression level. TROP2 promotes robust lactate production via the YBX1\u2010HIF\u20101\u03b1 signal axis. Targeting glycolytic flux decreases H3K18 lactylation and curbs TROP2\u2010driven CRLM colonisation and progression. Mechanistically, ChIP\u2010seq detection reveals H3K18la deposition at a set of pro\u2010metastatic gene promoters, promoting their expression. Crucially, TROP2\u2010induced H3K18la is found in turn sustaining TROP2 expression, forming a positive feedback loop that further accelerated metastatic progression. Pharmacologic HIF\u20101\u03b1 inhibition with acriflavine, an old FDA\u2010approved agent, suppresses TROP2\u2010high CRLM progression in multiple pre\u2010clinical models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, we establish H3K18la as a crucial epigenetic driver of TROP2\u2010mediated CRLM progression and propose that disrupting the H3K18la\u2013TROP2 feedback loop offers a novel therapeutic strategy against CRC metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>H3K18la is specifically increased in CRC cells in response to TROP2 signalling and drives TROP2\u2010mediated CRLM progression<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Genome\u2010wide analysis shows H3K18la deposition at the promoters of metastasis\u2010promoting genes drives their expression in TROP2\u2010high CRC.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Lactate sustains TROP2 expression in CRC cells via H3K18la<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Acriflavine suppresses TROP2\u2010driven CRLM by targeting the H3K18la\/TROP2 feedback loop<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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