The "double-edged sword" effect of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of endometriosis (EMS)

Abstracts Background Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to alleviate pain associated with endometriosis (EMS), yet the impact of their long-term use on disease progression remains unclear. This study investigates the dual role of NSAIDs in EMS pathogenesis using network toxicology and Mendelian randomization (MR). Methods The toxicity and ADMET profiles of nine NSAIDs were screened using ProTox 3.0 and ADMETlab 2.0. Potential drug targets were predicted using PharmMapper, STITCH, and SwissTargetPrediction, while EMS-related targets were retrieved from GeneCards, OMIM, and CTD databases. For the MR analysis, cis-eQTLs for whole blood tissue from GTEx v8 served as instrumental variables, based on the inflammatory nature of endometriosis. Outcome data were from an independent GWAS summary dataset (19,588 cases, 213,669 controls). Our analysis adhered to MR independence assumptions, ensuring no sample overlap between exposure and outcome data. Functional enrichment and molecular docking explored the underlying mechanisms. Results By integrating drug targets with disease genes, we first identified 463 overlapping targets. We revealed that EPHB4 is a core hub mediating the potential “risk-promoting” effects of nearly all NSAIDs, with its functions enriched in key pathological processes such as angiogenesis. Molecular docking confirmed that eight NSAIDs could stably bind to EPHB4. Crucially, we found that indomethacin exhibited a unique “dual-regulatory” pattern: it simultaneously targeted the protective target PTGER4 and the risk-associated target EPHB4. Molecular docking further substantiated, at the atomic level, that indomethacin possesses strong binding affinity for both targets, providing a structural biology explanation for its observed genetic effects. Interpretation This study provides, for the first time, robust causal evidence from both genetic and structural biology perspectives for the “double-edged sword” attribute of NSAIDs in EMS, and proposes a new paradigm of “target-oriented heterogeneous effects.” We found that specific NSAIDs might inadvertently promote disease progression by activating the EPHB4 pathway, while indomethacin stands out as a key exception due to its unique dual-action mechanism. These findings not only offer a critical explanation for the current clinical controversy but also lay a solid scientific foundation for advancing EMS management from “empirical medication” towards “precision-based selection guided by molecular mechanisms.” Graphical abstract