ZNF146 accelerates lung adenocarcinoma progression through MDM2/p53 and PHGDH/ferroptosis.

BACKGROUND: Lung adenocarcinoma (LUAD) remains a significant contributor to cancer incidence and mortality, with transcription factors playing pivotal roles in its progression and serving as potential therapeutic targets. RESULTS: Through an extensive analysis of expression data from over a thousand LUAD samples, we identified zinc finger protein 146 (ZNF146) as a transcription factor significantly overexpressed in LUAD, closely associated with poor patient outcomes. Functional studies using knockout and re-expression experiments in LUAD cell lines confirmed that ZNF146 robustly promotes cell proliferation. RNA-seq and ChIP-seq data integration further revealed two key downstream effectors of ZNF146: murine double minute 2 homolog (MDM2) and phosphoglycerate dehydrogenase (PHGDH). Our results demonstrated that ZNF146 accelerates LUAD progression via the MDM2/p53 pathway and PHGDH-mediated regulation of ferroptosis. CONCLUSIONS: Our findings indicate that targeting ZNF146 could be an effective strategy in treating LUAD, supported by evidence from adeno-associated virus-mediated inhibition of ZNF146, which suppressed tumor growth in patient-derived organoids and xenograft models. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-025-01433-7.