UHRF1 inhibits cuproptosis in lung adenocarcinoma via promoting FDX1 promoter methylation.

BACKGROUND

UHRF1 is a key epigenetic regulator implicated in the tumorigenesis of various cancers through DNA methylation; however, its specific mechanisms in the progression of lung adenocarcinoma (LUAD) remain poorly understood. This study aims to elucidate the regulatory role of UHRF1 in LUAD, focusing on its impact on cuproptosis.

METHODS

UHRF1 expression and its correlation with patient prognosis were analyzed using the TCGA-LUAD dataset. Expression levels of UHRF1 and FDX1 in LUAD cell lines were verified via qPCR and Western blot. Gene Set Enrichment Analysis (GSEA) was employed to explore UHRF1-associated pathways. The impact of UHRF1 on cuproptosis was assessed using CCK-8 assays, metabolite detection, and apoptosis analysis. Mechanistically, Chromatin Immunoprecipitation (ChIP) and Methylation-Specific PCR (MSP) were performed to investigate the binding and methylation status of the FDX1 promoter. Finally, the oncogenic role of UHRF1 was validated in vivo using a xenograft mouse model.

RESULTS

Clinical analysis revealed that elevated UHRF1 expression in LUAD tissues is significantly associated with poor prognosis. At the cellular level, UHRF1 overexpression downregulated FDX1 expression and inhibited DLAT oligomerization. Functional enrichment analysis indicated that UHRF1 is involved in metabolic reprogramming; specifically, its overexpression enhanced glycolysis while suppressing cuproptosis. Mechanistic studies demonstrated that UHRF1 binds directly to the FDX1 promoter, inducing hypermethylation and subsequent transcriptional silencing. Rescue experiments confirmed that restoring FDX1 expression reverses the cuproptosis-suppressive effects of UHRF1. In vivo, UHRF1 knockdown retarded tumor growth and promoted cell death, whereas concurrent FDX1 knockdown attenuated these tumor-suppressive effects.

CONCLUSION

UHRF1 negatively regulates FDX1 expression through DNA methylation, thereby inhibiting cuproptosis and driving LUAD progression. These findings clarify a novel epigenetic mechanism underlying LUAD and highlight the UHRF1/FDX1 axis as a potential therapeutic target.