Abstract
Acute myeloid leukemia (AML), a heterogeneous malignancy with complex molecular mechanisms, urgently requires improved prognostic biomarkers and therapeutic targets. This study investigated Hippocalcin-like 1（HPCAL1）, a calcium-binding protein with dual functionality dependent on cancer type, as a potential prognostic marker and investigated its interaction with the tumor immune microenvironment in AML. Through analyses of multiple independent cohorts (GSE13159, GSE34184, GSE24395 and institutional data), we revealed that significant HPCAL1 overexpression in AML samples was correlated with poor survival outcomes. ESTIMATE analysis revealed increased immune activity in the HPCAL1-high group, which was supported by differential expression profiling, which identified 617 genes enriched in inflammatory/immune pathways. Coexpression network and protein interaction analyses further implicated HPCAL1 in immune regulation, particularly through NOD-like receptor signaling, as confirmed by GSEA/GSVA. Single-cell RNA sequencing analysis of the GSE130756 dataset revealed monocyte-specific HPCAL1 expression with altered cellular communication patterns in AML, whereas deconvolution analysis revealed that increased monocyte proportions in HPCAL1-high samples were associated with adverse prognoses. Our findings establish HPCAL1 as a novel prognostic indicator in AML, potentially by mediating its effects through immune microenvironment modulation and monocyte population dynamics. These results provide a foundation for future mechanistic studies exploring the role of HPCAL1 in AML pathogenesis and its therapeutic potential.