Breast cancer remains a leading global health challenge, with treatment resistance posing significant obstacles to effective therapy. Emerging research highlights the pivotal role of dietary polyunsaturated fatty acids (PUFAs) and gut microbiota in modulating breast cancer progression and therapeutic outcomes. This review explores the interplay and potential relevance of the PUFA-microbiota-ferroptosis axis in breast cancer progression and therapy. Omega-3 PUFAs, abundant in diets like the Mediterranean, exhibit anti-inflammatory properties, promote beneficial gut microbiota, and enhance ferroptosis, thereby reducing tumor proliferation and resistance. Conversely, omega-6 PUFAs, prevalent in Western diets, can exacerbate inflammation and tumor aggressiveness when imbalanced. Gut microbiota, through the production of short-chain fatty acids and PUFA-derived metabolites, further regulate ferroptosis sensitivity and systemic inflammation. We are evaluating the mechanisms by which omega-3 PUFAs and probiotics restore gut dysbiosis, modulate the tumor microenvironment, and synergize with treatments like chemotherapy and immune checkpoint inhibitors. Taken together and considering the generally favorable safety profile of omega-3 PUFAs, these findings suggest that the PUFA-microbiota-ferroptosis axis may represent a promising avenue for further investigation as a complementary strategy to address treatment resistance and improve outcomes. This warrants further translational research to optimize its clinical utility in personalized breast cancer management. Regulatory frameworks are also crucial to ensuring the safe and ethical implementation of PUFA-based interventions in global breast cancer care.
