Background: Endometriosis is traditionally conceptualized as a localized gynecological disorder characterized by the presence of ectopic endometrial tissue. However, high recurrence rates following apparently complete surgical excision challenge this lesion-based paradigm and suggest the existence of underlying biological mechanisms that extend beyond residual disease. Increasing evidence indicates that endometriotic cells exhibit persistent molecular alterations, including dysregulated gene expression, epigenetic modifications, and immune dysfunction, which may contribute to disease maintenance and recurrence. Objective: This study aims to critically examine whether endometriosis can be considered a molecularly reprogrammed disease, characterized by persistent cellular and microenvironmental alterations that are not reversed by surgical removal of visible lesions. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science databases including studies published from January 2016 to March 2026. Studies investigating molecular, genetic, epigenetic, and immunological mechanisms of endometriosis persistence and recurrence were included. Particular attention was given to pathways involved in cellular survival, inflammation, hormone resistance, and epigenetic regulation. Results: Endometriotic cells demonstrate stable alterations in gene expression profiles, including pathways related to estrogen signaling, progesterone resistance, inflammation, and cellular proliferation. Epigenetic mechanisms, such as aberrant DNA methylation and histone modifications, appear to sustain these changes over time, contributing to a form of “molecular memory.” In parallel, the peritoneal microenvironment is characterized by chronic inflammation, immune tolerance, and impaired clearance of ectopic cells. These factors collectively support lesion persistence and may explain recurrence even after complete surgical excision. Emerging evidence also highlights the role of systemic factors, including endocrine–immune interactions and microbiome-related pathways, reinforcing the concept of endometriosis as a systemic rather than purely localized condition. Conclusions: Endometriosis may be more accurately defined as a persistent, molecularly reprogrammed disease driven by stable alterations in cellular behavior and the surrounding microenvironment. This paradigm shift has important clinical implications, suggesting that surgical treatment alone may be insufficient and that future therapeutic strategies should target the underlying molecular and immunological mechanisms responsible for disease persistence.
Palumbo et al. (Thu,) studied this question.