LncRNA-GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3

Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX induced cardiotoxicity. Bone mesenchymal stem cell-derived exosomes (BMSC Exos) and endothelial progenitor cells derived exosomes(EPC Exos) have a protective role in the myocardium. Here we found that BMSC Exos could improve DOX induced cardiotoxicity by inhibiting pyroptosis, but EPC Exos could not. Compared with EPCs Exo, BMSC Exo overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod like receptor protein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA binding protein 1 (IGF2BP1), a non catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC Exo ameliorated DOX induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3.