Premature ovarian failure (POF) is a pathological condition characterised by the decline of ovarian function in women under the age of 40. It is closely associated with decreased fertility, elevated risks of osteoporosis and cardiovascular diseases, and has emerged as a significant clinical issue affecting women's reproductive health and quality of life. Current research indicates that granulosa cell (GC), as key components of the follicular microenvironment, can accelerate follicular atresia through abnormal apoptosis, thereby contributing to the onset and progression of POF. In recent years, advances in molecular biology and omics technologies have facilitated deeper investigation into the mechanisms of GC apoptosis. Studies have revealed that its regulation involves multi level factors: at the protein level, the BCL 2 family and the Caspase cascade constitute the core module of apoptosis execution; at the signaling pathway level, pathways such as Wnt/β catenin, death receptor signaling, Hippo, and PI3K/AKT/mTOR interact through crosstalk to coordinately regulate GC apoptosis. In addition, epigenetic modifications, oxidative stress, hormonal imbalances, and inflammatory microenvironments collectively contribute to the initiation and progression of GC apoptosis. Hence, this review systematically summaries the signaling pathways, key proteins, and underlying regulatory mechanisms related to GC apoptosis, to elucidate its role in the pathogenesis of POF. This work seeks to provide novel theoretical perspectives on the pathological mechanisms of POF and to offer a reference for developing targeted intervention strategies aimed at regulating GC apoptosis.

1. Chon SJ, Umair Z, Yoon MS. Premature ovarian insufficiency: past, present, and future[J]. Front Cell Dev Biol, 2021, 9: 672890.

2. Tucker EJ, Grover SR, Bachelot A, et al. Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum[J]. Endocr Rev, 2016, 37(6): 609-635.

3. Schütz LF, Batalha IM. Granulosa cells: central regulators of female fertility[J]. Endocrines, 2024, 5(4): 547-565.

4. Liu SH, Jia YB, Meng SR, et al. Mechanisms of and potential medications for oxidative stress in ovarian granulosa cells: a review[J]. Int J Mol Sci, 2023, 24(11): 9205.

5. Li LY, Shi XJ, Shi Y, et al. The signaling pathways involved in ovarian follicle development[J]. Front Physiol, 2021, 12: 730196.

6. He RM, Liu YF, Fu WJ, et al. Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression[J]. Mol Cancer, 2024, 23(1): 267.

7. Hong Q, Fan MM, Cai R, et al. SOX4 regulates proliferation and apoptosis of human ovarian granulosa-like tumor cell line KGN through the Hippo pathway[J]. Biochem Biophys Res Commun, 2024, 705: 149738.

8. Wang SQ, Lin SJ, Zhu MM, et al. Acupuncture reduces apoptosis of granulosa cells in rats with premature ovarian failure via restoring the PI3K/AKT signaling pathway[J]. Int J Mol Sci, 2019, 20(24): 6311.

9. 刘小虎, 赵志慧, 周玥, 等. PI3K/Akt/mTOR自噬通路在人参皂苷Rg1延缓D-gal诱导的卵巢早衰小鼠模型卵巢早衰中的作用 [J]. 中国中药杂志, 2020, 45(24): 6036-6042. [Liu XH, Zhao  ZH, Zhou Y, et al. Effect of ginsenoside Rg_1 in delaying premature ovarian failure induced by D-gal in mice through PI3K/Akt/mTOR autophagy pathway[J]. China Journal of Chinese Materia Medica, 2020, 45(24): 6036-6042.]

10. Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death[J]. Cell Death Differ, 2018, 25(1): 65-80.

11. Regan SLP, Knight PG, Yovich JL, et al. Granulosa cell apoptosis in the ovarian follicle-a changing view[J]. Front Endocrinol (Lausanne), 2018, 9: 61.

12. Chen W, Dong L, Wei CF, et al. Role of epigenetic regulation in diminished ovarian reserve[J]. J Assist Reprod Genet, 2025, 42(2): 389-403.

13. Dong SC, Jiang SW, Hou BW, et al. miR-128-3p regulates follicular granulosa cell proliferation and apoptosis by targeting the growth hormone secretagogue receptor[J]. Int J Mol Sci, 2024, 25(5): 2720.

14. Voros C, Varthaliti A, Mavrogianni D, et al. Epigenetic alterations in ovarian function and their impact on assisted reproductive technologies: a systematic review[J]. Biomedicines, 2025, 13(3): 730.

15. Li M. The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases[J]. Apoptosis, 2021, 26(5-6): 235-247.

16. Chen J, Yang S, Ma BC, et al. Di-isononyl phthalate induces apoptosis and autophagy of mouse ovarian granulosa cells via oxidative stress[J]. Ecotoxicol Environ Saf, 2022, 242: 113898.

17. Wang JY, Wu JJ, Zhang YM, et al. Growth hormone protects against ovarian granulosa cell apoptosis: alleviation oxidative stress and enhancement mitochondrial function[J]. Reprod Biol, 2021, 21(2): 100504.

18. Tariq A, Seekford ZK, Bromfield JJ. Inflammation during oocyte maturation reduces developmental competence and increases apoptosis in blastocy[J]. Biol Reprod, 2025, 112(3): 420-433.

19. Liu LQ, Fang YY. The role of ovarian granulosa cells related-ncRNAs in ovarian dysfunctions: mechanism research and clinical exploration[J]. Reprod Sci, 2025, 32(7): 2098-2120.

20. Fan YT, Chang YJ, Wei L, et al. Apoptosis of mural granulosa cells is increased in women with diminished ovarian reserve[J]. J Assist Reprod Genet, 2019, 36(6): 1225-1235.

21. 王云迪, 吉日嘎拉赛罕·巴达日其, 王煜. 早发性卵巢功能不全遗传因素中相关基因改变的研究进展[J]. 生殖医学杂志, 2024, 33(6): 831-836. [Wang YD, Jargalsaikhan B, Wang Y. Advances in research on genetic changes related to premature ovarian insufficiency[J]. Journal of Reproductive Medicine, 2024, 33(6): 831-836.]

22. Zhang YX, Wu QQ, Bai FR, et al. Granulosa cell-specific FOXJ2 overexpression induces premature ovarian insufficiency by triggering apoptosis via mitochondrial calcium overload[J]. J Ovarian Res, 2025, 18(1): 75.

23. Jiao X, Zhang XR, Li NY, et al. Treg deficiency-mediated TH 1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells[J]. Clin Transl Med, 2021, 11(6): e448.

24. Wen F, Liu D, Wang M, et al. Celastrol induces premature ovarian insufficiency by inducing apoptosis in granulosa cells[J]. Biomed Pharmacother, 2023, 169: 115815.

25. Dong L, Wu HC, Qi FH, et al. Non-coding RNA-mediated granulosa cell dysfunction during ovarian aging: from mechanisms to potential interventions[J]. Noncoding RNA Res, 2025, 12: 102-115.

26. 卢苑蓉, 王强, 刘隽阳, 等. 基于PI3K/Akt信号通路探讨归肾育宫汤对早发性卵巢功能不全大鼠卵巢颗粒细胞自噬的影响 [J]. 现代中西医结合杂志, 2023, 32(24): 3359-3363, 3370. [Lu YR, Wang  Q, Liu JY, et al. Effect of Guishen Yugong decoction on autophagy of ovarian granulosa cells in rat of premature ovarian insufficiency bvia PI3K/AKT signaling pathway[J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2023, 32(24): 3359-3363, 3370.]

27. Yang YX, Tang XT, Yao T, et al. Metformin protects ovarian granulosa cells in chemotherapy-induced premature ovarian failure mice through AMPK/PPAR-γ/SIRT1 pathway[J]. Sci Rep, 2024, 14(1): 1447.

28. Zhou GH, He YF, Wang HL, et al. Exogenous melatonin alleviates premature ovarian failure by regulating granulosa cell autophagy[J]. NPJ Regen Med, 2025, 10(1): 35.

29. Duan HW, Yang SS, Yang S, et al. The mechanism of curcumin to protect mouse ovaries from oxidative damage by regulating AMPK/mTOR mediated autophagy[J]. Phytomedicine, 2024, 128: 155468.

30. Yu MM, Liu JX. MicroRNA-30d-5p promotes ovarian granulosa cell apoptosis by targeting Smad2[J]. Exp Ther Med, 2020, 19(1): 53-60.

31. 吴洁, 刘彦礼, 秦艺璐, 等. 骨髓间充质干细胞来源外泌体的微小RNA-22-3p参与抑制环磷酰胺诱导卵巢颗粒细胞损伤的机制研究[J]. 实用临床医药杂志, 2024, 28(4): 39-44. [Wu J, Liu YL, Qin YL, et al. Mechanism of microRNA-22-3p of extracellular vesicles derived from bone marrow mesenchymal stem cells in inhibiting damage of ovarian granulosa cells induced by cyclophosphamide[J]. Journal of Clinical Medicine in Practice, 2024, 28(4): 39-44.]

32. Chen XH, He HZ, Long BC, et al. Acupuncture regulates the apoptosis of ovarian granulosa cells in polycystic ovarian syndrome-related abnormal follicular development through LncMEG3-mediated inhibition of miR-21-3p[J]. Biol Res, 2023, 56(1): 31.

33. Ali I, Padhiar AA, Wang T, et al. Stem cell-based therapeutic strategies for premature ovarian insufficiency and infertility: a focus on aging[J]. Cells, 2022, 11(23): 3713.

34. Berkel C. Inducers and inhibitors of pyroptotic death of granulosa cells in models of premature ovarian insufficiency and polycystic ovary syndrome[J]. Reprod Sci, 2024, 31(10): 2972-2992.

35. Gajos-Michniewicz A, Czyz M. Therapeutic potential of natural compounds to modulate WNT/β-catenin signaling in cancer: current state of art and challenges[J]. Int J Mol Sci, 2024, 25(23): 12804.

36. 朱文倩, 张慧敏, 李磊, 等. 激活的富血小板血浆对卵巢储备功能降低患者卵丘颗粒细胞凋亡和增殖的影响[J]. 生殖医学杂志, 2022, 31(5): 652-660. [Zhu WQ, Zhang HM, Li L, et al. Effects of activated platelet rich plasma on apoptosis and proliferation of cumulus granulosa cells in patients with diminished ovarian reserve[J]. Journal of Reproductive Medicine, 2022, 31(5): 652-660.]