Autophagy and Lysosomal Dysregulation in Endometriosis: Therapeutic Opportunities and Molecular Insights

Endometriosis is a chronic estrogen-dependent inflammatory condition caused by the presence of endometrium-like tissue outside the uterus. It can cause pelvic pain, infertility, and a reduction in quality of life. Despite being a very common disorder, there is still a lack of understanding of the molecular pathogenesis of endometriosis, which has hampered the development of effective targeted therapies. Recent studies have revealed that dysregulation of autophagy and lysosomal function are critical drivers of disease pathogenesis. Autophagy is a highly conserved, highly regulated process of intracellular degradation that is essential for cellular homeostasis. Dysregulated autophagic flux within endometriotic lesions, particularly in ectopic endometrial epithelial and stromal cells, promotes cell survival in the face of oxidative and inflammatory stressors. Lysosomal dysfunction, as evidenced by altered enzyme activity and impaired acidification, further promotes lesion persistence, angiogenesis, and immune evasion. Estrogen signaling, pro-inflammatory mediators, and hormone resistance also modulate the autophagy–lysosome axis, further exacerbating disease pathogenesis. In this review, we provide an overview of the emerging molecular links between autophagy-lysosomal dysregulation and endometriosis. We evaluate the therapeutic potential of modulating these pathways in endometriosis. Pharmacological agents such as mTOR inhibitors, AMPK activators, natural autophagy inducers, and lysosomal modulators have shown promise in restoring autophagic and lysosomal function. These approaches may offer new non-hormonal therapeutic options and reduce recurrence in patients with refractory disease. A better understanding of the interplay between hormonal regulation, immune responses, and intracellular degradation pathways is critical for improving personalized therapies for endometriosis. Similar content being viewed by others Data Availability The data used or analyzed are all in this published article.

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Acknowledgments The author extends his appreciation to Ongoing Research Funding project (ORF-2026-17), at King Saud University, Riyadh, Saudi Arabia. Funding No specific funding was sought for the current study. Author information Authors and Affiliations Contributions A.H. Harrath: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Methodology, Investigation, Formal analysis. Corresponding author Ethics declarations Ethics Approval and Consent to Participate Not applicable. Consent for Publication Not applicable. Competing Interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Harrath, A.H. Autophagy and Lysosomal Dysregulation in Endometriosis: Therapeutic Opportunities and Molecular Insights. Reprod. Sci. 33, 691–709 (2026). https://doi.org/10.1007/s43032-026-02068-w Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-026-02068-w