Targeting Cuproptosis-Regulated Metabolism in Acute Myeloid Leukemia through Integrative Computational Analysis

Cuproptosis is a newly identified mode of programmed cell death involving copper-induced mitochondrial impairment, which is significantly influenced by components of the pyruvate dehydrogenase (PDH) complex. While there has been limited investigation into the impact of cuproptosis in patients with acute myeloid leukemia (AML), we used an integrative in silico methodology to assess the contribution of cuproptosis-associated metabolic members, such as DLD, DLAT, PDHA1, and PDHB, to AML. Analyses to assess expression profiles, dependencies, protein–protein interaction (PPI), enrichment of functions, and infiltration by immune cells were performed using publicly available databases. Furthermore, structure-based investigations, including density functional theory (DFT) calculations, molecular docking, molecular dynamics simulations, principal component analysis (PCA), dynamic cross-correlation matrix (DCCM), binding free energy estimations, meta-dynamics, and replica exchange, were employed to evaluate the biological activity of shikonin against the selected targets using cytarabine as a reference compound. Results showed significant upregulation of DLD, DLAT, and PDHA1 in AML samples compared with controls, while interaction network and pathway analyses highlighted their central roles in mitochondrial energy metabolism and pyruvate dehydrogenase complex (PDC) regulation. Survival and immune correlation analyses demonstrated their clinical relevance and association with immune microenvironment modulation. Docking and static binding energy calculations (Prime MM/GBSA) indicated that shikonin exhibits binding affinity comparable to that of the reference compound. However, ensemble-based free energy calculations and molecular dynamics-derived analyses, including PCA and DCCM, supported by enhanced sampling methods such as meta-dynamics and replica exchange simulations, revealed that the PDHA1-cytarabine complex demonstrates comparatively greater structural stability and conformational rigidity. Shikonin, in contrast, displayed stable binding with increased conformational flexibility. Overall, these studies provide a framework for understanding the relationship between cuproptosis-related metabolic regulation and AML, and suggest that shikonin may interact with AML-related mitochondrial metabolic targets and represents a potential candidate for further experimental validation.