biostudies-literatureKim YMinistry of Trade, Industry and EnergySwiss National Science FoundationEuropean Research CouncilKorea Drug Development FundMinistry of Health and WelfareMinistry of Science, ICT and Future PlanningÉcole Polytechnique Fédérale de LausanneKorea Ministry of Science and ICTNational Research Foundation of Korea101054https://www.ebi.ac.uk/biostudies/studies/S-EPMC10935544biostudies-literatureUnknown73<h4>Aims</h4>Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance.<h4>Methods</h4>Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib.<h4>Results</h4>SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1β inhibition.<h4>Conclusions</h4>SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapyInhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.PMC109355442021R1A6A3A13044725NRF-2017K1A1A2013124ERC-AdG-787702SNSF 31003A_179435RS-2023-00283539Kim DVerbeek JLee CWLee JKim KRJung HJKim YHNam SJung KYKim KHKang BEPandit NXu PKwon JAuwerx JShong MYi HSRyu DHa KTBae SJSchoonjans KKim YGariani KJo YGariani JfalseInhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.<h4>Aims</h4>Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance.<h4>Methods</h4>Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib.<h4>Results</h4>SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1β inhibition.<h4>Conclusions</h4>SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.2024-01-01T00:00:00Z2024 Mar2026-06-01T05:31:36.358Z2025-02-19T04:42:13.168ZS-EPMC109355443827775610.1016/j.drup.2024.101054