Exosomal miR-196a-5p Secreted by Bone Marrow Mesenchymal Stem Cells Inhibits Ferroptosis and Promotes Drug Resistance of Acute Myeloid Leukemia

Background: Ferroptosis is a nonapoptotic type of cell death characterized by an increase in lipid Reactive Oxygen Species (ROS). Acute myeloid leukemia (AML)-derived bone marrow mesenchymal stem cells (AML-BMSCs) support the progression and drug resistance of AML by secreting various bioactive substances, including exosomes. However, the role of BMSCs in regulating lipid metabolism and Ferroptosis in AML remains unexplored. Results: Exosomes secreted by AML-BMSCs increased the expression of miR-196a-5p in AML cells. MiR-196a-5p promoted the proliferation of AML cells, reduced lipid ROS and Ferroptosis, and was associated with poor prognosis in AML patients. Mechanistically, miR-196a-5p inhibited the expression level of neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L). Co-immunoprecipitation (CO-IP) analysis showed that NEDD4L was bound to long-chain acyl-CoA synthetase (ACSL)3 and promoted ubiquitin-mediated degradation of ACSL3 protein. In addition, we also demonstrated that AML-BMSCs highly expressed Ras-associated binding protein 7A (RAB7A), which was associated with exosomal miR-196a-5p release. Importantly, cytarabine (Ara-C) activated the expression of RAB7A and promoted the secretion of exosomal miR-196a-5p, which weakened the ubiquitination of ACSL3 by NEDD4L, leading to Ferroptosis inhibition and Ara-C resistance in AML. Innovation: This is the first time that exosomes secreted by BMSCs (BMSCs-exos) have been linked to Ferroptosis in AML cells, thereby expanding our understanding of the mechanism of drug resistance in AML cells. High miR-196a-5p expression reduced lipid ROS levels and Ferroptosis in AML cells by inhibiting NEDD4L-mediated ubiquitination of ACSL3. Conclusion: This study identified a new network through which BMSCs-exos regulate Ferroptosis in AML cells. We combined BMSCs and AML cells to provide new ideas for drug research targeting exosome secretion and Ferroptosis. Antioxid. Redox Signal. 42, 933-953.

AML; bone marrow mesenchymal stem cells; exosome; ferroptosis; miR-196a-5p.