MCL-1 Drives a Metabolic Dependency on Fatty Acid Oxidation in Cancer Independent of its Anti-Apoptotic Function

MCL-1 is an anti-apoptotic BCL-2 family protein essential to the survival of diverse cell types and is a major driver of cancer and chemoresistance. The unique oncogenic supremacy of MCL-1, as compared to its anti-apoptotic homologs, suggests that it has additional functions to complement apoptotic suppression. Here, we find that MCL-1-dependent hematologic cancer cells selectively rely on fatty acid oxidation (FAO) as a fuel source due to metabolic wiring enforced by MCL-1 itself. Importantly, this metabolic function is independent of anti-apoptotic activity, as demonstrated by metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking pro-apoptotic BAX and BAK. Genetic deletion of Mcl-1 results in selective downregulation of proteins within the FAO pathway, accompanied by cell death upon glucose deprivation despite apoptotic blockade. Our data reveal that MCL-1 drives a programmatic dependency on FAO in hematologic cancer cells, which can be effectively targeted by FAO inhibitors.