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

<b><i>Background:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Innovation:</i></b> 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. <b><i>Conclusion:</i></b> 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. <i>Antioxid. Redox Signal.</i> 42, 933-953.