Wei_2026_Int.J.Gen.Med_19_591023

BACKGROUND: Acute myeloid leukemia (AML) remains a therapeutic challenge, necessitating the identification of novel targets and repurposable drugs. This study integrates multi-omics and Mendelian randomization (MR) to investigate the role of lysosomal acid lipase (LIPA) in AML and to explore the potential of lovastatin as a LIPA-targeting agent. METHODS: We combined transcriptomic data from TCGA and GTEx with MR analysis using eQTLs to assess the causal relationship between LIPA expression and AML risk. A prognostic signature was constructed via LASSO and validated in external GEO cohorts. Network pharmacology, molecular docking, and molecular dynamics simulations were employed to identify drugs targeting LIPA. In vitro, AML cell lines (THP-1, K562) were treated with lovastatin and/or the ER stress inhibitor 4-PBA; apoptosis, ER stress markers, and ultrastructure were assessed by flow cytometry, qPCR, Western blot, and transmission electron microscopy. RESULTS: MR established a causal link between elevated LIPA expression and increased AML risk (OR=1.32, p=0.003). A 16-gene prognostic signature including LIPA effectively stratified patients (p<0.0001). Lovastatin was identified as a potential high-affinity LIPA inhibitor. In vitro, lovastatin induced marked apoptosis in AML cells, which was accompanied by downregulation of ER stress markers (ATF6, CHOP, IRE1) and constricted ER morphology. Notably, the ER stress inhibitor 4-PBA phenocopied these effects, consistent with lovastatin exerting its anti-AML activity through suppression of ER stress. CONCLUSION: This multi-omics study establishes LIPA as a causal prognostic biomarker in AML and reveals that lovastatin triggers apoptosis by inhibiting ER stress, providing a mechanistic rationale for repurposing lovastatin in AML therapy.