Shigetomi Hiroshi, Nishio Miki, Umetani Mai, Imanaka Shogo, Hashimoto Hiratsugu, Kobayashi Hiroshi
Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Japan.
Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, 3-3-17 Kitatomigaoka-cho, Nara 634-0001, Japan.
Int J Mol Sci. 2025 Sep 18;26(18):9125. doi: 10.3390/ijms26189125.
Endometriosis is a chronic disease characterized by the ectopic presence of endometrial cells that evade apoptosis and survive and proliferate under harsh environmental conditions. It is closely associated with infertility and pregnancy-related complications. This review focuses on the molecular pathophysiology of endometriosis, particularly the disruption of the p53-AMPK-mTOR signaling axis, and highlights the dysregulation of decidualization and cellular senescence, incorporating recent findings in reproductive physiology. A comprehensive literature search was conducted using PubMed and Google Scholar without temporal restrictions. Endometriotic cells adapt to the hostile peritoneal environment through resistance to apoptosis and alterations in autophagy. In the early stages, autophagy activation may promote cell survival; however, as the disease progresses, autophagic activity tends to decline. Aberrant activation of mTOR signaling is implicated in this process, contributing to the suppression of autophagy, impaired decidualization, and promotion of cellular senescence, ultimately facilitating lesion progression and infertility. Indeed, in the eutopic endometrium of patients with endometriosis, progesterone resistance, elevated inflammatory cytokines, and epigenetic abnormalities are known to reduce endometrial receptivity. Moreover, suppression of autophagy leads to excessive cellular senescence and secretion of the senescence-associated secretory phenotype (SASP), thereby interfering with proper decidualization. Maintaining an appropriate balance between decidualization and cellular senescence is essential for reproductive function. Future development of therapeutic strategies targeting these processes is expected to help overcome infertility associated with endometriosis.
子宫内膜异位症是一种慢性疾病，其特征是子宫内膜细胞异位存在，这些细胞逃避凋亡，在恶劣的环境条件下存活并增殖。它与不孕症和妊娠相关并发症密切相关。本综述重点关注子宫内膜异位症的分子病理生理学，特别是p53-AMPK-mTOR信号轴的破坏，并强调蜕膜化和细胞衰老的失调，纳入了生殖生理学的最新发现。使用PubMed和谷歌学术进行了无时间限制的全面文献检索。子宫内膜异位细胞通过对凋亡的抵抗和自噬的改变来适应恶劣的腹腔环境。在早期阶段，自噬激活可能促进细胞存活；然而，随着疾病进展，自噬活性往往会下降。mTOR信号的异常激活与这一过程有关，导致自噬受到抑制、蜕膜化受损和细胞衰老加剧，最终促进病变进展和不孕。事实上，在子宫内膜异位症患者的在位内膜中，已知孕激素抵抗、炎性细胞因子升高和表观遗传异常会降低子宫内膜容受性。此外，自噬的抑制会导致过度的细胞衰老和衰老相关分泌表型（SASP）的分泌，从而干扰正常的蜕膜化。在蜕膜化和细胞衰老之间保持适当的平衡对于生殖功能至关重要。针对这些过程的治疗策略的未来发展有望帮助克服与子宫内膜异位症相关的不孕症。
