Follistatin‐like 1 protects against doxorubicin‐induced cardiotoxicity by preventing mitochondrial dysfunction through the SIRT6/Nrf2 signaling pathway

Abstract Mitochondrial dysfunction and myocardial remodeling have been reported to be the main underlying molecular mechanisms of doxorubicin‐induced cardiotoxicity. SIRT6 is a nicotinamide adenine dinucleotide‐dependent enzyme that plays a vital role in cardiac protection against various stresses. Moreover, previous studies have demonstrated that FSTL1 could alleviate doxorubicin‐induced cardiotoxicity by inhibiting autophagy. The present study investigated the probable mechanisms of FSTL1 on doxorubicin‐induced cardiotoxicity in vivo and in vitro. We confirmed that FSTL1 exerted a pivotal protective role on cardiac tissue in vivo and on doxorubicin‐induced cell injury in vitro. Furthermore, FSTL1 can alleviate doxorubicin‐induced mitochondrial dysfunction by inhibiting autophagy and apoptosis. Further studies demonstrated that FSTL1 can activate SIRT6 signaling by restoring the SIRT6 protein expression in doxorubicin‐induced myocardial injury. SIRT6 activation elevated the protein expression of Nrf2 in doxorubicin‐induced H9C2 injury. Treatment with the Nrf2 inhibitor ML385 partially antagonized the cardioprotective role of SIRT6 on doxorubicin‐induced autophagy or apoptosis. These results suggested that the protective mechanism of FSTL1 on doxorubicin‐induced cardiotoxicity may be related with the inhibition of autophagy and apoptosis, partly through the activation of SIRT6/Nrf2.