Downregulation of DDIT4 levels with borneol attenuates hepatotoxicity induced by gilteritinib

Abstract

Gilteritinib, a multi-target kinase inhibitor, is currently used as standard therapy for acute myeloid leukemia. However, approximately half of the patients encounter liver-related adverse effects during the treatment with gilteritinib, which limiting its clinical applications. The underlying mechanisms of gilteritinib-induced hepatotoxicity and the development of strategies to prevent this toxicity are not well-reported. In our study, we utilized JC-1 dye, and MitoSOX to demonstrate that gilteritinib treatment leads to hepatocytes undergoing p53-mediated mitochondrial apoptosis. Furthermore, qRT-PCR analysis revealed that DNA damage-inducible transcript 4 (DDIT4), a downstream target of p53, was upregulated following gilteritinib administration and was identified as a key factor in gilteritinib-induced hepatotoxicity. After drug screening and western blot analysis, borneol, a bicyclic monoterpenoid, was found to decrease the protein level of DDIT4. This is the first compound found to downregulate DDIT4 levels and ameliorate hepatic injury caused by gilteritinib. Our findings suggest that high levels of DDIT4 are the primary driver behind gilteritinib-induced liver injury, and that borneol could potentially be a clinically safe and feasible therapeutic strategy by inhibiting DDIT4 levels.