HMGCLL1 (3-hydroxy-3-methylglutaryl-CoA lyase like 1) is a non-mitochondrial enzyme that catalyzes the cleavage of HMG-CoA into acetyl-CoA and acetoacetate, supporting ketogenesis and energy production in extrahepatic tissues 1. Unlike the classical mitochondrial HMG-CoA lyase, HMGCLL1 localizes to the cytosolic side of the endoplasmic reticulum membrane and cytosol in a myristoylation-dependent manner 12. The enzyme demonstrates kinetic properties comparable to its mitochondrial counterpart but shows higher substrate affinity and is particularly expressed in brain, lung, and kidney tissues 23. Transcriptionally, HMGCLL1 is consistently downregulated across 33 human cancer types, suggesting association with poor clinical outcomes 4. In chr6 myeloid leukemia, HMGCLL1 genetic variants serve as a predictive biomarker for deep molecular response to imatinib therapy; HMGCLL1 blockade reduces BCR-ABL1-positive cell viability and induces G0/G1 cell cycle arrest 5. Additionally, HMGCLL1 downregulation correlates with anticancer effects in breast cancer and represents a biomarker in schizophrenia pathology involving energy metabolism dysfunction 67. The functional roles of extramitochondrial HMGCLL1 beyond classical ketogenesis remain incompletely understood.