Spermidine suppresses oxidative stress and ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway to alleviate ovarian damage

Chunyang Niu; Dongmei Jiang; Yongni Guo; Zelong Wang; Qian Sun; Xin Wang; Weikang Ling; Xiaoguang An; Chengweng Ji; Shuo Li; Hua Zhao; Bo Kang

doi:10.1016/j.lfs.2023.122109

Spermidine suppresses oxidative stress and ferroptosis by Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway to alleviate ovarian damage

Life Sci. 2023 Nov 1:332:122109. doi: 10.1016/j.lfs.2023.122109. Epub 2023 Sep 21.

Authors

Chunyang Niu¹, Dongmei Jiang¹, Yongni Guo¹, Zelong Wang¹, Qian Sun¹, Xin Wang¹, Weikang Ling¹, Xiaoguang An¹, Chengweng Ji¹, Shuo Li¹, Hua Zhao², Bo Kang³

Affiliations

¹ State Key Laboratory of Swine and Poultry Breeding Industry, Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.
² Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
³ State Key Laboratory of Swine and Poultry Breeding Industry, Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China. Electronic address: bokang@sicau.edu.cn.

PMID: 37741320
DOI: 10.1016/j.lfs.2023.122109

Abstract

Aims: Oxidative stress is considered to be one of the culprits of ovarian dysfunction. Spermidine (SPD) is a natural aliphatic polyamine that is widely present in living organisms and has been shown to exert preventive effects on various ageing-related diseases. This study seeks to investigate the potential preventive and protective effects of SPD on ovarian oxidative damage.

Main methods: Ovarian oxidative stress model in C57BL/6 mice was established by 3-nitropropionic acid. Female mice were administrated 10 mg/kg or 15 mg/kg SPD. The estrous cycle, serum hormone levels and mating test were measured to evaluate ovarian function. Follicle counts and AMH levels to assess ovarian reserve. Masson's trichrome to assess ovarian fibrosis. TUNEL analysis to evaluate follicular granulosa cells (GCs) apoptosis. Oxidative stress and autophagy indicators (Nrf2, HO-1, GPX4, LC3B, P62) were measured in vivo and in vitro. RNA-sequencing was performed on SPD-treated GC to study the effects of SPD on Akt and FHC/ACSL4 signaling.

Key findings: SPD supplementation improved ovarian endocrine function and reproductive capacity in oxidative stress mice. SPD regularized the estrous cycle and alleviated oxidative stress. Furthermore, SPD increased the ovarian reserve, reducing GC apoptosis by activating the Nrf2/HO-1/GPX4 pathway. RNA-sequencing showed that SPD induced 230 genes changes in porcine GC, which were mainly involved in oocyte meiosis, arginine biosynthesis and glutathione metabolism pathways. SPD attenuated H₂O₂-induced ferroptosis by regulating Akt/FHC/ACSL4 signaling.

Significance: SPD alleviates oxidative stress and ferroptosis by regulating the Nrf2/HO-1/GPX4 and Akt/FHC/ACSL4 pathway, which may be a novel potential strategy to protect ovarian oxidative damage.

Keywords: Autophagy; Ferroptosis; GPX4 signaling; Ovary; Oxidative stress; Spermidine.