Aspartame exposure promotes endometriosis progression through PTGS2-mediated oxidative stress and mitochondrial dysfunction

Jixin Li, J N Li, Li J, Hu X, Xinya Hu, Cuishan Guo, Guo C, Wei Xue, Xue W, Wu J, Jiahui Wu, Yang M, Mengyi Yang, Wang J, Jiarui Wang, Qiao J, Junze Qiao, Zhu X, Xinyao Zhu, Lingbo Meng, Meng L, X Y Zhou, Xin Zhou, Zhou X
Ecotoxicology and environmental safety · 2026 · vol. 321 , pp. 120456 · doi:10.1016/j.ecoenv.2026.120456 · PMID:42385372 · W7166872499
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Aspartame exposure promotes endometriosis by targeting PTGS2, which mediates oxidative stress and mitochondrial dysfunction, leading to altered immune homeostasis.

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Abstract

BACKGROUND: Aspartame, a widely used artificial sweetener, has been implicated in multiple toxicities. However, its potential reproductive toxicity mechanisms remain unclear. This study aimed to investigate the underlying relationship between aspartame exposure and endometriosis pathogenesis. METHODS: Following the toxicity analysis of aspartame, we compiled its toxicity targets and simultaneously retrieved endometriosis-related genes. By intersecting these two gene lists, we identified the aspartame-induced endometriosis genes and enriched their biological functions and pathways. Subsequently, we established core targets by PPI network and topological analysis alongside machine learning algorithms and detected expression patterns of these hub genes in bulk and single-cell datasets. Finally, molecular docking and dynamics simulations were conducted to assess the interaction stability between aspartame and core targets, followed by in vitro and in vivo validation, and virtual gene knockout technology to elucidate the underlying molecular mechanisms. RESULTS: Firstly, we identified a total of 124 targets for aspartame and 3344 genes related to endometriosis. And we constructed an aspartame-endometriosis-genes regulatory network comprising 40 intersecting targets, among which five significantly differentially expressed targets were searched: ACE, DPP4, MME, IL1B, and PTGS2, and projected these genes onto a single-cell dataset to reveal their distribution patterns. Molecular docking and dynamics simulations identified PTGS2 as the core target exhibiting the most stable interaction with aspartame. Cellular and mice experimental validation further demonstrated that aspartame exposure promoted endometriosis progression by modulating oxidative stress and mitochondrial dysfunction, while PTGS2 knockdown and pharmacological inhibition partially reversed these aspartame-induced cellular phenotypes. Additionally, virtual gene knockout analysis suggested that PTGS2 perturbation disrupted immune-related gene networks, implicating altered intercellular communication and immune homeostasis in aspartame-associated endometriosis. CONCLUSION: Taken together, our study firstly established association between aspartame exposure and endometriosis pathogenesis, identified PTGS2 as a key target gene mediated by aspartame in endometriosis, proposed its underlying mechanisms of action, and analyzed the clinical value and significance.

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MeSH descriptors

Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame Aspartame

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (53)

SciLite annotations

chemicals 12
aspartame aspartame aspartame aspartame aspartame aspartame aspartame aspartame aspartame aspartame aspartame aspartame
organisms 1
mus sp.

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