Targeting the HERV-K102 Envelope Elicits Pyroptosis and Represents a Novel Therapeutic Strategy for Acute Myeloid Leukemia

Objective Human endogenous retroviruses (HERVs) have been the focus of numerous recent studies. HERVs entered the human genome millions of years ago and are associated with various diseases, including cancer and immune regulation. Among them, the HERV-K family exhibits the highest transcriptional activity. However, little is known about the expression of HERVs in acute myeloid leukemia (AML) or their potential as biomarkers and therapeutic targets. This study primarily investigated the role of HERV-K102 in the development of AML and explored its underlying mechanisms. Methods The expression profiles of HERV K102 in AML and normal samples were analyzed using The Cancer Genome Atlas (TCGA) database and AML cell lines. Knockout models were generated through CRISPR-Cas9-mediated deletion of the HERV-K102 envelope (K-ENV). Cell viability and pyroptosis rates were measured using the CCK-8 assay and flow cytometry, respectively. Transcriptome analysis was performed to identify differentially expressed genes and related pathways. Western blotting and detection of pyroptosis markers were conducted. Furthermore, the role of HERV-K102 in AML was validated in an inducible knockout xenograft tumor model. Results HERV-K102 was aberrantly activated and highly expressed in AML, and its expression correlated with poor prognosis. K-ENV depletion inhibited AML cell proliferation and promoted apoptosis. Moreover, K-ENV knockout induced pyroptosis, as indicated by increased lactate dehydrogenase (LDH) release, enhanced cleavage of caspase-1 and gasdermin D (GSDMD), and characteristic morphological features of pyroptotic cells. Mechanistically, transcriptomic and functional analyses demonstrated that this process was mediated by S100A9 upregulation and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. Conclusions Our findings suggest that HERV-K102 ENV plays a critical role in AML pathogenesis and may represent a novel diagnostic and therapeutic target.