Genetically predicted inflammatory mediators link mitochondrial function to breast cancer risk: A Mendelian randomization study

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. 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. 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. 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. • An integrated analytical framework combining Mendelian randomization (MR), mediation, and bioinformatics revealed a potential “mitochondria-inflammation” interactome underlying breast cancer risk. • The protective effect of 39S ribosomal protein L33 (MRPL33) is partially counteracted by C-C motif chemokine ligand 25 (CCL25), while the risk-promoting effect of NADH dehydrogenase (ubiquinone) iron-sulfur protein 4 (NDUFS4) is self-attenuated via cluster of differentiation 5 (CD5), revealing opposing mitochondria-immune feedback loops. • Enrichment analyses linked the identified proteins and factors to key pathways, including interleukin-17 (IL-17) signaling and cytokine-cytokine receptor interaction, suggesting novel immunometabolic regulatory axes. • In silico drug-target predictions identified repurposable candidates (e.g., Methotrexate, Tamoxifen) for potentially modulating the newly identified pathogenic axes. • Targeting mitochondrial-related proteins and inflammatory factors together may represent a new strategy for precision medicine and immunotherapy in breast cancer.