Abstract / Summary
Abstract Acute myeloid leukemia is a highly heterogeneous hematologic malignancy with an extremely poor prognosis. Although the BCL-2 inhibitor venetoclax introduced a new therapeutic option for patients, its widespread resistance substantially limited clinical application, and the underlying molecular mechanisms remained incompletely understood. By comparing single-cell transcriptomic profiles before and after venetoclax treatment, we found that GPR56 was markedly upregulated in post-treatment AML samples and was strongly associated with venetoclax resistance in clinical cohorts. Mechanistically, GPR56 activated the RhoA–ROCK1–MAX axis to upregulate PGC-1α expression, thereby enhancing mitochondrial biogenesis and counteracting venetoclax-induced mitochondrial toxicity. The small-molecule GPR56 inhibitor DHM effectively restored venetoclax sensitivity in AML cells. Collectively, this study supports a potential role for GPR56-mediated mitochondrial regulation in venetoclax resistance and suggests that targeting GPR56 may represent a candidate therapeutic strategy to improve venetoclax efficacy in AML.