Dietary restriction genes as modulators of breast cancer risk through metabolic pathways.

[BACKGROUND] Breast cancer is a highly heterogeneous disease shaped by both genetic predispositions and environmental influences. While substantial advancements have been achieved in treatment, issues such as tumor recurrence and resistance to therapy continue to hinder effective, personalized prevention strategies. Dietary restriction—a modifiable lifestyle factor—has shown promise in cancer prevention by influencing metabolic pathways and immune function. Nevertheless, the contribution of genes associated with dietary restriction to breast cancer susceptibility remains largely unclear.

[METHODS] Differential expression analysis of 276 dietary restriction-related genes, including 1,080 breast cancer samples and 99 normal controls, was conducted using RNA sequencing data from The Cancer Genome Atlas. To assess the causal relationships between dietary restriction genes and metabolic indicators (LDL HDL, BMI, WC, and TG), genetic variants associated with these indicators were examined. Protein‒protein interaction networks were constructed to identify key interactions, and potential therapeutic compounds were predicted through the DSigDB database. Molecular docking was subsequently performed to evaluate the binding affinities between these compounds and the proteins encoded by dietary restriction-related genes.

[RESULTS] A total of 86 dietary restriction-related genes were significantly associated with breast cancer, with seven shared SNP loci identified in conjunction with metabolic indicators, providing evidence of a potential causal relationship. KEGG and GO enrichment analyses revealed that these genes regulate longevity pathways and lipid metabolism, influencing breast cancer development. PPI analysis revealed core regulatory nodes, and drug prediction highlighted several candidate compounds, including perfluoroundecanoic acid and rifampicin, with strong binding affinities to dietary restriction-related proteins. In vitro experiments demonstrated that perfluoroundecanoic acid has protective effects against breast cancer oncogenesis.

[CONCLUSIONS] This study suggests a potential causal relationship between dietary restriction-related genes and breast cancer, revealing their significant association with tumour development and metabolic regulation and identifying perfluoroundecanoic acid as a candidate for further investigation in breast cancer prevention. These findings offer new insights for precision prevention strategies and adjunct lifestyle-based clinical management in patients with breast cancer, contributing to the broader goal of reducing the global burden of this prevalent disease.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12944-026-02883-9.