Genetically predicted inflammatory mediators link mitochondrial function to breast cancer risk: A Mendelian randomization study
Cancer Pathogenesis and Therapy, 2026
Ran L., Feng J., Chen J., Wang J., Liu J., Zhu X.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Background
The interplay between mitochondrial dysfunction and chronic inflammation is an emerging frontier in breast cancer research, yet their causal relationships and interactive mechanisms remain unclear.
Methods
We performed two-step Mendelian randomization(MR) to evaluate causal and mediating effects of 70 mitochondrial-related proteins and 91 inflammatory factors on breast cancer and its estrogen receptor (ER) subtypes. Key findings were further explored through protein-protein interaction networks, functional enrichment, prognostic analysis, immune infiltration analysis, drug target and sensitivity prediction, and phenome-wide association studies.
Results
Ten mitochondria-related proteins and fifteen inflammatory factors showed suggestive causal associations with breast cancer risk. Mediation analysis revealed that 39S ribosomal protein L33 (MRPL33) exerts a protective effect on overall breast cancer (inverse-variance weighted [IVW] OR=0.978, P=0.023) was partially counteracted by the upregulation of C-C motif chemokine ligand 25 (CCL25) (mediation proportion: –7.01%), while NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) exerts a risk-promoting effect on overall breast cancer (IVW OR=1.017, P=0.009) and ER-positive (ER+) breast cancer (IVW OR=1.017, P=0.031) was partially attenuated by cluster of differentiation 5 (CD5) downregulation (mediation proportions: –9.69% and –15.01%, respectively). Bioinformatics analyses further revealed prognostic associations and immune-metabolic pathway functions of these molecules, and identified potential drugs and combination therapies based on preclinical and clinical data.
Conclusion
This study provides genetic evidence for the mitochondria-inflammation axis in breast cancer risk. Integrative analyses reveal novel pathogenic pathways and potential intervention targets, providing genetic evidence to support immune-metabolic regulation in breast cancer.