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. 2025 Mar 4;37(3):673-691.e7.
doi: 10.1016/j.cmet.2024.11.010. Epub 2024 Dec 26.

Adipocyte-derived ferroptotic signaling mitigates obesity

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Free article

Adipocyte-derived ferroptotic signaling mitigates obesity

Xue Wang et al. Cell Metab. .
Free article

Abstract

Ferroptosis is characterized as an iron-dependent and lipophilic form of cell death. However, it remains unclear what role ferroptosis has in adipose tissue function and activity. Here, we find a lower ferroptotic signature in the adipose tissue of individuals and mice with obesity. We further find that activation of ferroptotic signaling by a non-lethal dose of ferroptosis agonists significantly reduces lipid accumulation in primary adipocytes and high-fat diet (HFD)-fed mice. Notably, adipocyte-specific overexpression of acyl-coenzyme A synthetase long-chain family member 4 (Acsl4) or deletion of ferritin heavy chain (Fth) protects mice from HFD-induced adipose expansion and metabolic disorders via activation of ferroptotic signaling. Mechanistically, we find that 5,15-dihydroxyeicosatetraenoic acid (5,15-DiHETE) activates ferroptotic signaling, resulting in the degradation of hypoxia-inducible factor-1α (HIF1α), thereby derepressing a thermogenic program regulated by the c-Myc-peroxisome proliferator-activated receptor gamma coactivator-1 beta (Pgc1β) pathway. Our findings suggest that activating ferroptosis signaling in adipose tissues might help to prevent and treat obesity and its related metabolic disorders.

Keywords: 5,15-DiHETE; 5,15-dihydroxyeicosatetraenoic acid; ACSL4; HIF1α; acyl-coenzyme A synthetase long-chain family member 4; adipose tissue; ferritin; ferrology; ferroptosis; ferroptotic signaling; hypoxia-inducible factor-1α; iron metabolism; obesity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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