Rhythm gene PER1 mediates ferroptosis and lipid metabolism through SREBF2/ALOX15 axis in polycystic ovary syndrome

Yuanyuan Chen; Zhaohua Liu; Hongmei Chen; Yi Wen; Lang Fan; Man Luo

doi:10.1016/j.bbadis.2024.167182

Rhythm gene PER1 mediates ferroptosis and lipid metabolism through SREBF2/ALOX15 axis in polycystic ovary syndrome

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 21;1870(5):167182. doi: 10.1016/j.bbadis.2024.167182. Online ahead of print.

Authors

Yuanyuan Chen¹, Zhaohua Liu¹, Hongmei Chen¹, Yi Wen¹, Lang Fan¹, Man Luo²

Affiliations

¹ Reproductive Medicine Center, Hunan Provincial Maternal and Child Health Hospital (Hunan Provincial Reproductive Medicine Institution), Changsha, Hunan, China; The Affiliated Maternal and Child Health Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China.
² Reproductive Medicine Center, Hunan Provincial Maternal and Child Health Hospital (Hunan Provincial Reproductive Medicine Institution), Changsha, Hunan, China; The Affiliated Maternal and Child Health Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China. Electronic address: hunanivf@163.com.

PMID: 38653359
DOI: 10.1016/j.bbadis.2024.167182

Abstract

Objective: This work aimed to investigate the role of rhythm gene PER1 in mediating granulosa cell ferroptosis and lipid metabolism of polycystic ovary syndrome (PCOS).

Methods: We injected dehydroepiandrosterone and Ferrostatin-1 (Fer-1) into mice to explore the mechanism of ferroptosis in PCOS. The effect of PER1 on ferroptosis-like changes in granulosa cells was explored by overexpression of PER1 plasmid transfection and Fer-1 treatment.

Results: We found that Fer-1 ameliorated the characteristic polycystic ovary morphology, suppressed ferroptosis in the PCOS mice. PER1 and ALOX15 were highly expressed in PCOS, whereas SREBF2 was lowly expressed. Overexpression of PER1 decreased granulosa cell viability and inhibited proliferation. Meanwhile, overexpression of PER1 increased lipid reactive oxygen species, 4-Hydroxynonenal (4-HNE), Malondialdehyde (MDA), total Fe, and Fe²⁺ levels in granulosa cells and decreased Glutathione (GSH) content. Fer-1, SREBF2 overexpression, or ALOX15 silencing treatment reversed the effects of PER1 overexpression on granulosa cells. PER1 binds to the SREBF2 promoter and represses SREBF2 transcription. SREBF2 binds to the ALOX15 promoter and represses ALOX15 transcription. Correlation analysis of clinical trials showed that PER1 was positively correlated with total cholesterol, low-density lipoprotein cholesterol, luteinizing hormone, testosterone, 4-HNE, MDA, total Fe, Fe²⁺, and ALOX15. In contrast, PER1 was negatively correlated with SREBF2, high-density lipoprotein cholesterol, follicle-stimulating hormone, progesterone, and GSH.

Conclusion: This study demonstrates that the rhythm gene PER1 promotes ferroptosis and dysfunctional lipid metabolism in granulosa cells in PCOS by inhibiting SREBF2/ALOX15 signaling.

Keywords: ALOX15; Ferroptosis; Lipid metabolism; Polycystic ovary syndrome; Rhythm gene PER1; SREBF2.