Glycolytic reprogramming and MYH10 K1520 lactylation mediate eutopic endometrial collagen I deposition driven by PKM2-packaged ectopic endometrial extracellular vesicles.

Endometriosis (EMs) is characterized by ectopic lesions that disrupt endometrial decidualization, a process frequently accompanied by aberrant collagen deposition and closely linked to clinical infertility. Extracellular vesicles (EVs) are key mediators of intercellular communication and contribute to the pathogenesis and progression of EMs. However, whether EVs promote type I collagen deposition in the eutopic endometrium through glycolytic reprogramming and subsequent non-histone lactylation remains unclear. This study reveals that PKM2-carrying EVs derived from ectopic endometrial stromal cells (designated EMs-EVs) are transported via the systemic circulation to eutopic endometrial stromal cells and are internalized. This process upregulates PKM2 in the eutopic endometrium, triggering glycolytic reprogramming and lactate accumulation. The increased lactate level induces lactylation at lysine 1520 (K1520la) of myosin heavy chain 10 (MYH10). This modification not only upregulates α-smooth muscle actin (α-SMA) but also enhances the binding between MYH10 and α-SMA: an interaction essential for conferring contractile properties to stress fibers. Consequently, these events promote type I collagen deposition and contribute to defective decidualization in the eutopic endometrium. Collectively, our findings demonstrated that EMs-EVs drive endometrial collagen deposition through PKM2-mediated glycolytic reprogramming and subsequent MYH10 K1520 lactylation, thereby deepening our understanding of the role of impaired decidualization in the development of endometriosis-associated infertility.