Creatine promotes endometriosis progression by inducing M2 polarization of peritoneal macrophages

In brief: Endometriosis (EM) is a chronic inflammatory disease with unclear pathogenesis, in which peritoneal macrophages play a pivotal role. This study demonstrates that creatine (CR) induces M2 polarization of peritoneal macrophages, promoting angiogenesis, fibrogenesis and lesion progression in EM, offering new insight into potential therapeutic strategies. Abstract: EM is a chronic inflammatory disease characterized by the growth of endometrium-like tissues outside the uterine cavity, with an unclear pathogenesis. The analysis of single-cell sequencing data revealed the pivotal role of peritoneal macrophages in the development of EM. We noted significant CR enrichment and synthesis in peritoneal macrophages of patients with EM compared with women without EM. To further investigate the mechanisms of CR in EM, we performed RNA sequencing and in vitro experiments. We found that CR reprograms M2 polarization by enhancing matrix metalloproteinases and anti-inflammatory cytokines, which are involved in angiogenesis, fibrogenesis, cell adhesion and tissue repair. The coculture of CR-treated macrophages promoted the migration and fibrogenesis of endometrial stromal cells, as well as the angiogenesis of HUVECs in vitro. In summary, this article reveals that CR might polarize M2 macrophages, promoting the initiation, fibrosis and angiogenesis of ectopic endometrial lesions, ultimately resulting in the development of EM. These findings underscore the crucial immunomodulatory role of CR in the pathogenesis of EM, offering a promising target for therapeutic intervention.