Lean adipocyte oxylipin signaling restrains breast cancer through ferroptosis.

Obesity increases breast cancer risk and tumor aggressiveness, yet the mechanisms underlying this association remain unclear. In this work, we identify a tumor-suppressive lipid signaling pathway in which mammary adipocytes secrete the oxylipin 9S-hydroxyoctadecadienoic acid (9S-HODE). 9S-HODE induces ferroptosis in breast cancer cells by disrupting iron homeostasis. Adipocytes in obese mammary tissue produce less 9S-HODE, and tumors in obese mice exhibit reduced ferroptosis. Accordingly, ferroptosis inhibition accelerates tumor growth in lean mice, and restoring 9S-HODE suppresses tumor growth in obese mice. In humans, mammary 9S-HODE content is inversely correlated with body mass index, and 9S-HODE inhibits patient-derived breast cancer organoid growth. These findings identify the loss of adipocyte-derived 9S-HODE as a mechanism by which obesity promotes breast cancer and suggest that the restoration of ferroptosis-inducing lipid signaling may be a therapeutic strategy.