Abstract

Pelvic organ prolapse (POP) is a common gynecological disorder severely affecting quality of life, characterized by extracellular matrix (ECM) disruption and metabolic dysregulation. Lactylation is a lactate-induced post-translational modification that regulates gene expression, but its role in POP remains unclear. Here, we demonstrate that enhanced glycolysis and lactate accumulation drive histone lactylation, which impairs mitochondrial function and collagen biosynthesis in POP. Furthermore, we identify histone acetyltransferase Kat7 as a key lactyltransferase that catalyzes H3K14 and H3K18 lactylation via its glutamate residue E508. Notably, H3K14la/H3K18la suppresses the expression of Slc25a51, a mitochondrial NAD + transporter, leading to NAD + deficiency, hyperacetylation of P5CS, proline depletion, and inhibition of fibroblast proliferation. In vivo , inhibition of glycolysis or Kat7 activity ameliorates vaginal distension-induced lactylation, restores Slc25a51 expression, and improves collagen deposition. Taken together, these findings reveal that histone lactylation disrupts mitochondrial NAD + homeostasis and proline metabolism in fibroblasts, thus inhibiting collagen synthesis and enhancing POP pathogenesis. We show that histone H3 lactylation at K14 and K18 promotes POP progression. Kat7 catalyzes lactylation of histone H3 at K14 and K18, and this modification represses Slc25a51 expression, disrupts mitochondrial NAD + transport, and inhibits proline-dependent collagen synthesis. Targeting lactate production or Kat7 may restore mitochondrial function and ECM homeostasis, providing a potential treatment for POP.