GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE309nnn/GSE309897/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE309897GEOGSEfalseManipulation of Mitochondrial Metabolism Sensitizes AML to MCL-1 InhibitionMCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes such as those harboring KMT2A rearrangements (KMT2A-r). Clinical trials of MCL-1 inhibitors have been limited by modest efficacy and dose-limiting toxicity, underscoring the need for rational combination strategies. Here, we identify inhibition of electron transport chain complex I (CI) as a synthetic lethal partner for MCL-1 blockade. Mechanistically, CI suppression activates the mitochondrial stress arm of the integrated stress response (ISR), sensitizing leukemia cells to apoptosis upon MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML.2026/06/23GSE309897GSM9284619GSM9284625GSM9284614GSM9284624GSM9284613GSM9284612GSM9284623GSM9284622GSM9284618GSM9284629GSM9284628GSM9284617GSM9284616GSM9284627GSM9284615GSM9284626GSM9284621GSM928462024676309897Homo sapiens[42350371]