ZNF146-Mediated HMGB1-NF-κB Signaling Activation as a Therapeutic Target and Prognostic Biomarker in Osteosarcoma

This study aimed to investigate the role of ZNF146 in osteosarcoma progression and its potential as a therapeutic target and prognostic biomarker, focusing on its interaction with the HMGB1-NF-κB signaling pathway.

ZNF146 expression was analyzed in osteosarcoma tissues versus normal tissues using RNA-seq data from the TARGET database and validated in a cohort of 36 patients via RTqPCR, Western blot, and IHC. Functional assays (Transwell, wound healing, colony formation, CCK-8) and molecular analyses (dual-luciferase reporter, ChIP, Western blot) were conducted in MG63 and U2OS cells with ZNF146 modulation. An MG63 xenograft mouse model was used for in vivo validation.

ZNF146 was significantly upregulated in osteosarcoma tissues, correlating with poor patient prognosis (p =0.0307). Functionally, ZNF146 overexpression promoted cell proliferation, migration, and invasion, while its knockdown suppressed these effects. Mechanistically, ZNF146 directly binds to the HMGB1 promoter, thereby enhancing HMGB1 expression and activating the NF-κB pathway, which leads to increased cyclin D1 and MMP9 levels. In vivo, ZNF146 knockdown resulted in reduced tumor growth and Ki-67/PCNA expression.

These findings establish ZNF146 as a key oncogenic driver in osteosarcoma via HMGB1-NF-κB signaling. The results align with studies implicating ZNF proteins in tumor progression but highlight a novel mechanism. Limitations include unexplored effects on the tumor microenvironment and the need for validation in larger clinical cohorts.

ZNF146 promotes osteosarcoma progression through HMGB1-mediated NF-κB activation, suggesting its potential as both a prognostic biomarker and a therapeutic target. Inhibition of ZNF146 or HMGB1 may offer novel strategies for osteosarcoma treatment.