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

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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.

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