Sex Hormone Signaling Suppresses Ferroptosis via Phospholipid Remodeling

Ferroptosis is an iron-dependent mode of cell death characterized by membrane phospholipid peroxidation by intracellular free radicals, leading to plasma membrane rupture. Because low levels of lipid peroxidation can occur during cellular metabolism or in response to various acute environmental stressors, cells rely on negative regulators of ferroptosis, such as glutathione peroxidase 4 (GPX4), which reduces phospholipid peroxides, and ferroptosis suppressor 1 (FSP1), one of multiple enzymes that produce radical-trapping antioxidants. To investigate additional surveillance mechanisms that may suppress ferroptosis, Liang and colleagues performed a whole-genome CRISPR activation screen in human fibrosarcoma cells and identified membrane bound O-acyltransferase domain containing 2 (MBOAT2) as a negative regulator of ferroptosis that enabled cells to survive ferroptosis induction, independently of GPX4 and FSP1. Whereas polyunsaturated fatty acid (PUFA)–containing phospholipids are particularly susceptible to lipid peroxidation, MBOAT2 preferentially incorporates monounsaturated fatty acids (MUFA) into phospholipids, suggesting that MBOAT2 may suppress ferroptosis by competitively decreasing phospholipid PUFA content. Indeed, lipidomic analysis demonstrated that overexpression of MBOAT2 specifically increased MUFA-containing phosphatidyl­ethanolamine (PE) while decreasing PUFA-PE, and resistance to ferroptosis conferred by MBOAT2 required either endogenous or exogenous MUFAs. Analysis of MBOAT2 expression levels in tumor samples within The Cancer Genome Atlas indicated high levels of MBOAT2 in androgen receptor (AR)–positive prostate cancer, and chromatin immunoprecipitation analysis revealed that AR localized near the transcription start site of MBOAT2 and induced MBOAT2 expression. AR antagonism via enzalutamide sensitized a castration-resistant murine xenograft model to GPX4 knockout–mediated ferroptosis and cooperated with ferroptosis to induce tumor regression. Strikingly, assessment of other MBOAT family members for ferroptosis-regulating activity pointed to MBOAT1 as a ferroptosis suppressor, which is regulated by estrogen receptor (ER) signaling in breast cancer. Pharmacologic induction of ferroptosis sensitized an ER antagonist–resistant murine xenograft model to fulvestrant and cooperatively reduced tumor growth. Together, these findings highlight a sex hormone–regulated mechanism of ferroptosis suppression that may be exploited in therapeutic strategies to target AR⁺ prostate cancer and ER⁺ breast cancer.

Liang D, Feng Y, Zandkarimi F, Wang H, Zhang Z, Kim J, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 2023;186:2748–64.e22.

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