2026-04-13T04:42:13Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/699332025-12-26T11:28:57Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Tutusaus, Anna author Sanduzzi Zamparelli, Marco author Boix, Loreto author Rider, Patricia author Subías, Silvia author García de Frutos, Pablo author Colell, Anna author Marí, Montserrat author Reig, María author Morales, Albert author 2025-03-14T07:13:11Z 2025-03-14T07:13:11Z 2024 During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). 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-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β 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. This research was funded by Instituto de Salud Carlos III (ISCIII) through project PI22/00475 to M.M., FI19/00222 to M.S.-Z. and PI18/0358 to M.R., and co-funded by the European Union “ERDF A way of making Europe”; CIBEREHD, CIBERCV, and CIBERNED; Ministerio de Ciencia, Innovación y Universidades: grant numbers PID2021-123564OB-I00 and PDC2023-145806-I00 to A.M/P.G.F. and PID2022-143279OB-I00 to A.C. funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. AGAUR, grant number 2021_SGR_00490 to A.C.; Fundació la Marató de TV3 to A.M.; and CERCA Programme/Generalitat de Catalunya. ASC IL-1β NLRP3 Liver cancer Pyroptosis Tumor microenvironment Induction of the inflammasome pathway by tyrosine kinase inhibitors provides an actionable therapeutic target for hepatocellular carcinoma