Hypoxia activates the unfolded protein response signaling network: An adaptive mechanism for endometriosis

Yong Zhou, Yang Jin, Yuan Wang, Ruijin Wu
Frontiers in endocrinology · 2022 · vol. 13 , pp. 945578 · doi:10.3389/fendo.2022.945578 · PMID:36339404 · PMC9630844 · W4306945746
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Hypoxia activates the unfolded protein response signaling network, forming a complex regulatory mechanism that aids in the survival of ectopic endometrial cells in unfavorable microenvironments.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

This paper reviews how hypoxia is theorized to contribute to endometriosis by examining the “planting/implant” framework and related models of retrograde endometrial cell shedding into the peritoneal cavity. It describes that when endometrial fragments lose blood supply, acute hypoxia would normally trigger apoptosis and immune clearance, but in endometriosis these cells may instead adapt by increasing adhesion, invasion, angiogenesis, and altering immune clearance to resist death, with HIF-1α acting as a key hypoxia-responsive transcriptional regulator. The authors further argue that HIF-1α alone is insufficient to drive the full adaptive survival program, so the unfolded protein response (UPR) triggered by endoplasmic reticulum stress may provide an essential supplementary cytoprotective network. The main caveat is that the exact mechanisms by which hypoxia drives ectopic lesion establishment and persistence remain unclear, and the discussion is largely based on synthesized evidence and theory rather than new experimental results. This paper is centrally about endometriosis—specifically how hypoxia activates the HIF-1α and unfolded protein response signaling network to support survival of ectopic endometrial cells.

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Abstract

Endometriosis (EMS) is a chronic gynecological disease that affects women of childbearing age. However, the exact cause remains unclear. The uterus is a highly vascularized organ that continuously exposes endometrial cells to high oxygen concentrations. According to the "planting theory" of EMS pathogenesis, when endometrial cells fall from the uterine cavity and retrograde to the peritoneal cavity, they will face severe hypoxic stress. Hypoxic stress remains a key issue even if successfully implanted into the ovaries or peritoneum. In recent years, increasing evidence has confirmed that hypoxia is closely related to the occurrence and development of EMS. Hypoxia-inducible factor-1α (HIF-1α) can play an essential role in the pathological process of EMS by regulating carbohydrate metabolism, angiogenesis, and energy conversion of ectopic endometrial cells. However, HIF-1α alone is insufficient to achieve the complete program of adaptive changes required for cell survival under hypoxic stress, while the unfolded protein response (UPR) responding to endoplasmic reticulum stress plays an essential supplementary role in promoting cell survival. The formation of a complex signal regulation network by hypoxia-driven UPR may be the cytoprotective adaptation mechanism of ectopic endometrial cells in unfavorable microenvironments.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometrium

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