Histone lactylation-mediated overexpression of RASD2 promotes endometriosis progression via upregulating the SUMOylation of CTPS1.

Histone lactylation is crucial in a variety of physiopathological processes; however, the function and mechanism of histone lactylation in endometriosis remain poorly understood. Therefore, the objective of this investigation was to illuminate the function and mechanism of histone lactylation in endometriosis. Immunohistochemistry was used to investigate the expression of histone lactylation. Cell Counting Kit-8 assay (CCK8), Transwell assay, and endometriosis mouse models were used to investigate the effects of histone lactylation in vitro and in vivo. Transcriptomics and immunoprecipitation-mass spectrometry (IP-MS), Western blot, co-immunoprecipitation (Co-IP), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to explore the intrinsic mechanisms. In this study, we found that histone lactylation was upregulated in endometriosis and could promote endometriosis progression both in vivo and in vitro. Mechanistically, histone lactylation H3K18la promoted the transcription of Ras homolog enriched in striatum (RASD2), and RASD2, in turn, increased the stability of CTP synthase 1 (CTPS1) by promoting the SUMOylation and inhibiting the ubiquitination of CTPS1, thereby promoting endometriosis progression. Overall, our findings indicated that histone lactylation could promote the progression of endometriosis through the RASD2/CTPS1 axis. This investigation uncovered a novel mechanism and identified prospective targets for endometriosis diagnosis and therapy. Our finding reveals a novel mechanism that promotes the progression of endometriosis, namely the histone lactylation/RASD2/CTPS1 axis. This finding suggests that inhibiting histone lactylation or inhibiting RASD2 and CTPS1 might be a potential therapeutic strategy to inhibit endometriosis lesion growth.