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. 2024 Jul 21;14(7):876.
doi: 10.3390/biom14070876.

Assessment of the Ferroptosis Regulators: Glutathione Peroxidase 4, Acyl-Coenzyme A Synthetase Long-Chain Family Member 4, and Transferrin Receptor 1 in Patient-Derived Endometriosis Tissue

Lidia A Mielke Cabello  1 , Gabriela Meresman  2 , Dogus Darici  3 , Noelia Carnovale  2 , Birthe Heitkötter  4 , Miriam Schulte  4 , Nancy A Espinoza-Sánchez  1 , Quang-Khoi Le  1 , Ludwig Kiesel  1 , Sebastian D Schäfer  1 , Martin Götte  1
Affiliations

Assessment of the Ferroptosis Regulators: Glutathione Peroxidase 4, Acyl-Coenzyme A Synthetase Long-Chain Family Member 4, and Transferrin Receptor 1 in Patient-Derived Endometriosis Tissue

Lidia A Mielke Cabello et al. Biomolecules. .

Abstract

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, may contribute to the progression of endometriosis. This retrospective case-control study provides a comprehensive immunohistochemical assessment of the expression and tissue distribution of established ferroptosis markers: GPX4, ACSL4, and TfR1 in endometriosis patients. The case group consisted of 38 women with laparoscopically and histologically confirmed endometriosis and the control group consisted of 18 women with other gynecological conditions. Our study revealed a significant downregulation of GPX4 in stromal cells of endometriosis patients (M = 59.7% ± 42.4 versus 90.0% ± 17.5 in the control group, t (54) = -2.90, p = 0.005). This finding aligned with slightly, but not significantly, higher iron levels detected in the blood of endometriosis patients, using hemoglobin as an indirect predictor (Hb 12.8 (12.2-13.5) g/dL versus 12.5 (12.2-13.4) g/dL in the control group; t (54) = -0.897, p = 0.374). Interestingly, there was no concurrent upregulation of TfR1 (M = 0.7 ± 1.2 versus 0.2 ± 0.4 for EM, t (54) = 2.552, p = 0.014), responsible for iron uptake into cells. Our empirical findings provide support for the involvement of ferroptosis in the context of endometriosis. However, variances in expression patterns within stromal and epithelial cellular subsets call for further in-depth investigations.

Keywords: ACSL4; GPX4; TfR1; biomarkers; endometriosis; ferroptosis; iron.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Expression of GPX4. (A) Ectopic endometrium (vaginal wall) of endometriosis patient. (B) Eutopic endometrium of control. (C) Mouse testis as positive control. (D) Eutopic endometrium of control treated with an unrelated monoclonal antibody of the same isotype as negative control. ×400 magnification. Scale bar = 200 μm.
Figure 2
Figure 2
Expression of ACSL4. (A) Ectopic endometrium (ureter) of endometriosis patient. (B) Eutopic endometrium of control. (C) Mouse epididymis as positive control. (D) Ectopic endometrium (sacrouterine ligament) treated with an unrelated monoclonal antibody of the same isotype as negative control. ×400 magnification. Scale bar = 200 μm.
Figure 3
Figure 3
Expression of TfR1. (A) Ectopic endometrium (abdominal wall) of endometriosis patient. (B) Eutopic endometrium of control. (C) Mouse liver as positive control. (D) Eutopic endometrium of control treated with an unrelated monoclonal antibody of the same isotype as negative control. ×400 magnification. Scale bar = 200 μm.
Figure 4
Figure 4
Violin plots of the percentage (%) of stained cells. (A) Expression of GPX4 in stromal and epithelial cells of patients with endometriosis (EM) and controls (Ctrl). (B) Expression of ACSL4 in stromal and epithelial cells of endometriosis patients and controls. (C) Expression of TfR1 in stromal and epithelial cells of endometriosis patients and controls. ** p < 0.01; n.s. = not statistically significant.
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