Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo

Zhang, Shilin; Xu, Yan; Zhang, Jingxi; Liang, Qingsheng; Chen, Zhengdao; Zhang, Mengyue; Sun, Jingyu; Chen, Shaohong; Hu, Chuanyin; Zhao, Yun-Tao

doi:10.3390/ijms27114845

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Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo

by

Shilin Zhang

^1,†,

Yan Xu

^1,†,

Jingxi Zhang

¹,

Qingsheng Liang

¹,

Zhengdao Chen

¹,

Mengyue Zhang

¹,

Jingyu Sun

¹,

Shaohong Chen

¹,

Chuanyin Hu

^2,* and

Yun-Tao Zhao

^1,*

¹

Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Modern Biochemistry Experimental Center, Guangdong Ocean University, Zhanjiang 524088, China

²

Department of Biology, Guangdong Medical University, Zhanjiang 524023, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(11), 4845; https://doi.org/10.3390/ijms27114845

Submission received: 19 March 2026 / Revised: 18 May 2026 / Accepted: 25 May 2026 / Published: 27 May 2026

(This article belongs to the Section Bioactives and Nutraceuticals)

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Abstract

Premature ovarian insufficiency (POI) poses a serious risk to the reproductive health and psychological well-being of women. Here, the protective effects of hydroxytyrosol (HT), the primary phenolic component of olive oil, on POI were investigated. In vitro, human ovarian granulosa-like tumour cell lines (KGN cells) were challenged by D-galactose (D-gal) with or without HT. HT administration effectively alleviated KGN cell damage, decreased the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells, increased superoxide dismutase (SOD) activity, reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels, enhanced the expression level of Bcl-2, inhibited the expression level of Bax, and inhibited cell apoptosis in D-gal-treated KGN cells. In vivo, HT administration reversed the decreased ovarian index, oestrous cycle disruption, and abnormal sex hormone levels observed in D-gal-induced POI mice. HT administration increased glutathione (GSH) levels, reduced the MDA levels, and attenuated apoptosis in ovarian tissues, as evidenced by a decreased number of TUNEL-positive cells, upregulated Bcl-2 expression, and downregulated Bax expression. Mechanistically, HT downregulated the expression level of Kelch-like ECH-associated protein 1 (Keap1) and enhanced the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in vitro and in vivo. In conclusion, HT ameliorates D-gal-induced POI in vitro and in vivo by activating the Nrf2/HO-1 signalling pathway.

Keywords: apoptosis; granulosa cells; hydroxytyrosol; oxidative stress; premature ovarian insufficiency

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MDPI and ACS Style

Zhang, S.; Xu, Y.; Zhang, J.; Liang, Q.; Chen, Z.; Zhang, M.; Sun, J.; Chen, S.; Hu, C.; Zhao, Y.-T. Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo. Int. J. Mol. Sci. 2026, 27, 4845. https://doi.org/10.3390/ijms27114845

AMA Style

Zhang S, Xu Y, Zhang J, Liang Q, Chen Z, Zhang M, Sun J, Chen S, Hu C, Zhao Y-T. Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo. International Journal of Molecular Sciences. 2026; 27(11):4845. https://doi.org/10.3390/ijms27114845

Chicago/Turabian Style

Zhang, Shilin, Yan Xu, Jingxi Zhang, Qingsheng Liang, Zhengdao Chen, Mengyue Zhang, Jingyu Sun, Shaohong Chen, Chuanyin Hu, and Yun-Tao Zhao. 2026. "Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo" International Journal of Molecular Sciences 27, no. 11: 4845. https://doi.org/10.3390/ijms27114845

APA Style

Zhang, S., Xu, Y., Zhang, J., Liang, Q., Chen, Z., Zhang, M., Sun, J., Chen, S., Hu, C., & Zhao, Y.-T. (2026). Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo. International Journal of Molecular Sciences, 27(11), 4845. https://doi.org/10.3390/ijms27114845

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Hydroxytyrosol Enhances the Nrf2/HO-1 Signalling Pathway to Inhibit Oxidative Stress and Apoptosis and Improve Premature Ovarian Insufficiency In Vitro and In Vivo

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