Our integrative multi-omics analysis and cellular experiments reveal that AML cells surviving VEN treatment exhibit upregulated CD14 expression with concomitant sphingolipid metabolic rewiring, specifically marked by increased expression of ASAH1. Crucially, suppression of ASAH1 partially restored VEN sensitivity without altering monocytic differentiation markers, suggesting that ASAH1-mediated dysregulation of ceramide drives VEN resistance independently of monocytic phenotype in AML. The gene discussed is ASAH1; the disease is acute myeloid leukemia.