The effects of inhibiting IRE1α on the viability of ovarian granulosa cells

• Published in: Scientific reports Vol. 15; no. 1; pp. 19512 - 10
• Main Authors: Li, Chao, Tan, Yong-Peng, Meng, Tie-Gang, Gao, Di, Xu, Ke, Lu, You-Hui, Yi, Li-Tao, Liu, Shu-Chen, Wang, Guang, Sun, Qing-Yuan, Lei, Xiao-Can
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.06.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 4µ8c; 631/136; 631/80; 631/92; Apoptosis; Apoptosis - drug effects; APY29; Cell apoptosis; Cell cycle; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chaperones; DNA damage; DNA Damage - drug effects; Drug dosages; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - metabolism; Female; Females; Fertility; Flow cytometry; Granulosa cells; Granulosa Cells - cytology; Granulosa Cells - drug effects; Granulosa Cells - metabolism; Humanities and Social Sciences; Humans; IRE1α; Kinases; Medicine; Membrane potential; Membrane Potential, Mitochondrial - drug effects; multidisciplinary; Ovarian granulosa cells; Ovaries; Oxidative stress; Oxidative Stress - drug effects; Phosphorylation - drug effects; Physiology; Protein folding; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Proteins; Reproductive health; Science; Science (multidisciplinary); APY29; Ovarian granulosa cells; Chaperones; 4µ8c; IRE1α; Cell apoptosis
• DOI: 10.1038/s41598-025-03600-9
• ISSN: 2045-2322

IRE1α, a type I transmembrane protein characterized by a cytoplasmic serine/threonine kinase domain, is related to ER stress and ER function maintenance. In this study, 4µ8c, a highly effective selective inhibitor of IRE1α RNase, and APY29, an ATP competitive inhibitor, inhibiting IRE1α autophosphorylation and the kinase domain, were employed to elucidate the function of IRE1α on the proliferation of ovarian granulosa cells, with the ultimate goal of identifying novel strategies and methodologies for the prevention and treatment of associated diseases. Human ovarian granulosa cells (SVOG) cultured in vitro were treated with the IRE1α inhibitors 4µ8c and APY29. It was shown that inhibition of IRE1α reduced the cell ability of dealing with misfolded protein, triggered oxidative stress, altered mitochondrial membrane potential, and inflicted DNA damage, eventually lead to ovarian granulosa cell apoptosis.