Histone Lactylation Couples FSH-Driven Lactate Metabolism to Mitochondrial Biogenesis by Enhancing HDAC4-Mediated Deacetylation of PGC-1α in Granulosa Cells

Follicle-stimulating hormone (FSH) coordinates ovarian follicle development by aligning mitochondrial biogenesis with increased metabolic demand. Although FSH is known to stimulate glycolysis in granulosa cells (GCs), the mechanism by which glycolytic flux coupled to mitochondrial biogenesis remains unclear. Here, we demonstrate that histone lactylation functions as a lactate-sensitive epigenetic mediator linking FSH-driven metabolic alterations to mitochondrial biogenesis in GCs. Mechanistically, FSH increases intracellular lactate levels through glycolytic activation, thereby promoting P300/CBP-dependent lactylation of histone H4 at lysine 5 (H4K5la). H4K5la directly enhances HDAC4 expression, and HDAC4 subsequently deacetylates PGC-1α at lysine residues 329/330. Deacetylated PGC-1α cooperates with nuclear respiratory factors NRF1/2 to drive transcription of key mitochondrial regulators (<i>TFAM</i>, <i>TFB1M</i>, <i>TFB2M</i>), ultimately promoting mitochondrial biogenesis. Disruption of the H4K5la/HDAC4/PGC-1α axis markedly impaired mitochondrial biogenesis and follicular development, evidenced by reduced ovarian weight, smaller follicle size, decreased antral follicle number, and impaired GC proliferation and estradiol (E2) production in FSH-treated mice. These findings identify a metabolic-epigenetic regulatory pathway in which histone lactylation links glycolysis to mitochondrial adaptation, providing mechanistic insight into FSH-dependent reproductive physiology.