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Erastin-induced multi-pathway cell death in endometriosis: a mechanistic and translational narrative review
1School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Abstract:
This narrative review examines the therapeutic potential of Erastin and its derivatives for endometriosis (EMS) by integrating mechanistic, preclinical, and translational perspectives. We conducted a focused review of literature from PubMed and Web of Science Core Collection (WoSCC) through August 2025; following a systematic screening and de-duplication process, 91 studies were included for synthesis. The evidence indicates that within the iron-rich, ROS-prone microenvironment of EMS, Erastin inhibits the system Xc- transporter, depletes intracellular glutathione (GSH), and inactivates GPX4, thereby driving ferroptosis in ectopic endometrial stromal cells. This process engages a coordinated network of regulated cell death that extends beyond ferroptosis to include crosstalk with necroptosis and pyroptosis, while being critically modulated by ferritinophagy and the paradoxical role of defective mitophagy. Despite the development of next-generation analogs with improved pharmacological properties, clinical translation is constrained by a narrow therapeutic window due to on-target and off-target toxicities. To overcome these limitations, we propose that future strategies must prioritize lesion-focused drug delivery, such as nanocarriers and triggerable prodrugs, alongside biomarker-guided treatment regimens to decouple efficacy from systemic risk, paving a credible path for the clinical application of Erastin-class agents in EMS.
Insights
Erastin induces cell death in endometriosis by targeting the system Xc- transporter and glutathione. Future strategies for Erastin therapy in endometriosis require targeted delivery and biomarkers to manage toxicity.
Area of Science:
- Gynecological pathology
- Cellular biology
- Pharmacology
Background:
- Endometriosis (EMS) is a chronic, inflammatory gynecological condition.
- Current therapeutic options for endometriosis are limited.
- Erastin, a ferroptosis inducer, shows potential for endometriosis treatment.
Purpose of the Study:
- To review the therapeutic potential of Erastin and its derivatives for endometriosis.
- To integrate mechanistic, preclinical, and translational data on Erastin in EMS.
- To identify challenges and propose future strategies for clinical translation.
Main Methods:
- Systematic literature review of PubMed and Web of Science Core Collection (WoSCC) up to August 2025.
- Synthesis of 91 selected studies.
- Analysis of Erastin's mechanism of action in the context of the EMS microenvironment.
Main Results:
- Erastin inhibits system Xc-, depletes glutathione (GSH), and inactivates GPX4, inducing ferroptosis in ectopic endometrial stromal cells.
- Regulated cell death pathways, including necroptosis and pyroptosis, are involved and modulated by ferritinophagy and mitophagy.
- Next-generation analogs show improved properties, but clinical translation is limited by toxicity and a narrow therapeutic window.
Conclusions:
- Erastin effectively targets endometriosis via ferroptosis induction.
- Clinical application requires overcoming toxicity through targeted delivery (e.g., nanocarriers, prodrugs) and biomarker-guided regimens.
- Future strategies aim to decouple efficacy from systemic risk for Erastin-class agents in EMS.
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