L-carnosine attenuates endometrial fibrosis by targeting the ERK/PTGS2 axis

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.