GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE349nnn/GSE349088/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE349088GEOGSEfalseERK1/2 Inhibition Overcomes Resistance to Venetoclax in AML by Inhibiting Drp1-Dependent Mitochondrial Fission and Destabilizing Mcl-1 [scRNA-Seq 1]ERK1/2-mediated phosphorylation of Drp1 drives mitochondrial fission, stemness, and therapy resistance in RAS-driven solid tumors; however, its role in acute myeloid leukemia (AML) remains unclear. We identified ERK1/2-mediated Drp1 phosphorylation as a mechanism of resistance to venetoclax in AML. ERK1/2 inhibition using Compound 27 (ERKi), an analog of the clinical ERK1/2 inhibitor ASTX029, reduced mitochondrial fission, induced ROS accumulation, mitochondrial depolarization, and apoptosis in venetoclax-resistant AML cells. ERKi sensitized resistant AML cells to venetoclax and depleted leukemia progenitor cells in primary AML samples. Conversely, overexpression of Drp1-phosphomimetic restored mitochondrial fission and reversed apoptosis induced by venetoclax alone and in combination with ERKi. In post-venetoclax/decitabine relapsed human AML PDX model, co-treatment with venetoclax and ASTX029 improved survival and reduced leukemia burden accompanied by decreased pDrp1-Ser616, Mcl-1, and pMcl-1-Thr163 expression in bone marrow-derived human leukemic cells. In conclusion, inhibiting the ERK1/2-Drp1 axis overcomes resistance to venetoclax in AML.2026/09/30GSE349088GSM10086925GSM10086926GSM10086923GSM10086924GSM10086921GSM10086922GSM10086930GSM10086920GSM10086931GSM10086929GSM10086918GSM10086919GSM10086927GSM1008692828038349088Homo sapiens