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Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1\u03b2 after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1\u03b2 addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.<\/jats:p>","DOI":"10.3390\/cancers16081491","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T03:56:13Z","timestamp":1713153373000},"page":"1491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1133-321X","authenticated-orcid":false,"given":"Anna","family":"Tutusaus","sequence":"first","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Barcelona Clinic Liver Cancer (BCLC) Group, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sanduzzi-Zamparelli","sequence":"additional","affiliation":[{"name":"Barcelona Clinic Liver Cancer (BCLC) Group, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Liver Unit, Hospital Clinic de Barcelona, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain"},{"name":"Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6015-3901","authenticated-orcid":false,"given":"Loreto","family":"Boix","sequence":"additional","affiliation":[{"name":"Barcelona Clinic Liver Cancer (BCLC) Group, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Liver Unit, Hospital Clinic de Barcelona, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7604-1795","authenticated-orcid":false,"given":"Patricia","family":"Rider","sequence":"additional","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Sub\u00edas","sequence":"additional","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1547-1190","authenticated-orcid":false,"given":"Pablo","family":"Garc\u00eda de Frutos","sequence":"additional","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Unidad Asociada (IMIM), IIBB-CSIC, 08036 Barcelona, Spain"},{"name":"CIBERCV, ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5236-1834","authenticated-orcid":false,"given":"Anna","family":"Colell","sequence":"additional","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6116-3247","authenticated-orcid":false,"given":"Montserrat","family":"Mar\u00ed","sequence":"additional","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5711-9534","authenticated-orcid":false,"given":"Mar\u00eda","family":"Reig","sequence":"additional","affiliation":[{"name":"Barcelona Clinic Liver Cancer (BCLC) Group, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Liver Unit, Hospital Clinic de Barcelona, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain"},{"name":"Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8702-2269","authenticated-orcid":false,"given":"Albert","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Cell Death and Proliferation, IIBB-CSIC, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Barcelona Clinic Liver Cancer (BCLC) Group, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cucarull, B., Tutusaus, A., Rider, P., Hern\u00e1ez-Alsina, T., Cu\u00f1o, C., Garc\u00eda de Frutos, P., Colell, A., Mar\u00ed, M., and Morales, A. 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