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Updated: Jun 26, 2026
Establishing a Mouse Model of Thin Endometrium
Published on: November 1, 2024
L-carnosine attenuates endometrial fibrosis by targeting the ERK/PTGS2 axis
Yaru Zhu1, Xi'er Zhang1, Xinyu Zhang1
1Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
Aim:
Intrauterine adhesions (IUA) remain a significant clinical challenge, as current surgical interventions are limited by high recurrence rates. While metabolic dysregulation is implicated in various fibrotic diseases, its specific role in IUA pathogenesis remains largely unexplored. In this study, metabolomic analysis revealed a marked depletion of L-carnosine in IUA patients, prompting us to investigate its pathophysiological role and therapeutic potential.
Methods:
We evaluated the anti-fibrotic effects of L-carnosine in vitro using TGF-β-induced human endometrial stromal cells (hESCs) and in vivo using a mouse model of IUA. Subsequently, RNA-seq was performed on hESCs to compare the TGF-β-treated group with the TGF-β plus L-carnosine group, aiming to identify differentially expressed genes and enriched signaling pathways, thereby elucidating the molecular mechanisms by which L-carnosine attenuates endometrial fibrosis.
Results:
We demonstrated that L-carnosine treatment effectively reversed TGF-β-induced fibrosis in hESCs in vitro and attenuated uterine fibrosis in an IUA mouse model in vivo. Mechanistically, the anti-fibrotic effects of L-carnosine were mediated by the inhibition of ERK phosphorylation, which subsequently led to increased the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). The functional importance of this ERK/PTGS2 axis was validated: exogenous PGE2 (the major product of PTGS2) mimicked the anti-fibrotic effects, whereas inhibition of PTGS2 with celecoxib (a specific PTGS2 inhibitor) abrogated the protective effects of L-carnosine. Conversely, pharmacological activation of ERK using mSIRK (an ERK activator) blunted the L-carnosine-induced upregulation of PTGS2.
Conclusion:
These findings identify L-carnosine depletion as a pivotal metabolic hallmark of IUA and position L-carnosine supplementation as a viable anti-fibrotic strategy by specifically targeting the ERK/PTGS2 pathway.
Insights
L-carnosine depletion is linked to intrauterine adhesions (IUA). Supplementing L-carnosine shows anti-fibrotic effects by targeting the ERK/PTGS2 pathway, offering a potential treatment for IUA.
Area of Science:
- Reproductive biology
- Metabolomics
- Fibrosis research
Background:
- Intrauterine adhesions (IUA) present a significant clinical challenge with high recurrence rates after surgery.
- Metabolic dysregulation's role in IUA pathogenesis is under-explored, despite its implication in other fibrotic diseases.
- Metabolomic analysis revealed L-carnosine depletion in IUA patients.
Purpose of the Study:
- Investigate the pathophysiological role of L-carnosine in IUA.
- Evaluate the therapeutic potential of L-carnosine as an anti-fibrotic strategy for IUA.
- Elucidate the molecular mechanisms underlying L-carnosine's effects on endometrial fibrosis.
Main Methods:
- In vitro studies using TGF-β-induced human endometrial stromal cells (hESCs).
- In vivo studies using a mouse model of IUA.
- RNA-sequencing (RNA-seq) to identify differentially expressed genes and signaling pathways.
Main Results:
- L-carnosine reversed TGF-β-induced fibrosis in hESCs and attenuated uterine fibrosis in the IUA mouse model.
- L-carnosine's anti-fibrotic effects are mediated by inhibiting ERK phosphorylation and increasing PTGS2 expression.
- The ERK/PTGS2 pathway is crucial, as PGE2 mimicked L-carnosine's effects, while PTGS2 inhibition abrogated them.
Conclusions:
- L-carnosine depletion is a key metabolic feature of IUA.
- L-carnosine supplementation is a potential anti-fibrotic strategy for IUA.
- Targeting the ERK/PTGS2 pathway offers a novel therapeutic approach for IUA.