Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis

Curtin, M. C.; Jackson, A. E.; Brown, E. A.; Maschek, J. A.; Lum, D.; Cox, J.; Welm, A.; Hilgendorf, K. I.

doi:10.1101/2025.07.17.665258

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bioRxiv · 10.1101/2025.07.17.665258

Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis

Curtin, M. C.·Jackson, A. E.·Brown, E. A.·Maschek, J. A.·Lum, D.·Cox, J.·Welm, A.·Hilgendorf, K. I.

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Abstract

Obesity is predicted to become the largest modifiable risk factor for breast cancer in postmenopausal women, yet the mechanisms underlying this association are unclear. We identified a novel role for the endogenous oxylipin 9S-HODE, secreted by lean adipocytes, to induce ferroptosis in breast cancer cells while sparing normal breast epithelial cells. Obese adipocytes fail to secrete 9S-HODE, suggesting that the loss of ferroptosis induction significantly contributes to the acceleration of obesity-associated breast cancer. Consequently, the inhibition of ferroptosis accelerates breast cancer in lean, but not obese, mice. Further, 9S-HODE inhibits the growth of patient-derived breast cancer organoids, and supplementing 9S-HODE into tumors in obese mice is sufficient to reduce tumor burden, underscoring its potential as a therapeutic agent.

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Curtin, M. C., Jackson, A. E., Brown, E. A., Maschek, J. A., Lum, D., Cox, J., Welm, A., Hilgendorf, K. I.. 2025-07-21. Lean breast adipocytes secrete an oxylipin that suppresses breast cancer via ferroptosis. https://doi.org/10.1101/2025.07.17.665258

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