Lon peptidase 1 promotes proliferation and metastasis in breast cancer via interleukin 6 signaling.

INTRODUCTION: Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive behavior and lack of targeted therapies. Mitochondrial protease Lon Peptidase 1 (LONP1) has been associated with cancer progression; however, its clinical relevance and mechanistic role in triple-negative breast cancer (TNBC) remain unclear. This study investigates LONP1 as a potential prognostic biomarker and therapeutic target in breast cancer, with emphasis on TNBC. METHODS: We performed multi-omics analyses by integrating RNA-seq data from TCGA, GEO, and METABRIC cohorts. Functional studies were conducted using five breast cancer cell lines (BT-474, BT-549, MCF-7, MDA-MB-231 [TNBC], T-47D) with LONP1 knockdown or overexpression. Cell proliferation, migration, and invasion were assessed in vitro. In vivo tumorigenicity was evaluated in BALB/c nude mice. Mechanistic investigations included transcriptomic profiling and validation of IL-6 signaling using qPCR and Western blot. RESULTS: LONP1 was significantly overexpressed in TNBC versus non-TNBC tissues, correlating with advanced stage and poor survival. Functionally, LONP1 overexpression increased proliferation, migration, and invasion in models, while in vivo tumors exhibited accelerated growth. Transcriptomics revealed IL-6/JAK-STAT3 pathway activation, confirmed by upregulated IL-6 expression in LONP1-high cells. CONCLUSION: LONP1 promotes TNBC progression through IL-6-mediated oncogenic signaling, indicating its potential as both a prognostic biomarker and a therapeutic target in aggressive breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-025-04110-w.