Lactate Metabolic Restriction Is Linked to Granulosa Cell Dysfunction and Early Atresia‐Like Changes via H4K12la‐Mediated Epigenetic Remodeling and p53 Signaling in Goats

ABSTRACT

Lactate metabolism is a pivotal component of the follicular microenvironment, yet how altered lactate availability influences granulosa cell (GC) fate during early follicular atresia remains elusive. We found significantly lower lactate concentrations in the follicular fluid of atretic goat follicles compared to healthy counterparts. In vitro, pharmacological inhibition of lactate dehydrogenase (LDH) depleted intracellular lactate, leading to suppressed GC proliferation and G0/G1 arrest without increasing apoptosis. Notably, these proliferative defects were significantly attenuated by exogenous sodium L‐lactate supplementation, suggesting that lactate availability plays an important role in GC cell‐cycle progression. Transcriptomic profiling further indicated a broad suppression of cell‐cycle and DNA replication programs following LDH inhibition. At the epigenetic level, restricted lactate availability was associated with decreased global protein lactylation and specific reductions in histone H4 lysine 12 lactylation (H4K12la). Integrative analysis of CUT&Tag data identified the checkpoint regulator growth arrest and DNA damage‐inducible alpha (GADD45A) as a candidate target associated with altered H4K12la occupancy. CUT& RUN‐qPCR confirmed reduced H4K12la enrichment at the GADD45A promoter, while siRNA‐mediated GADD45A knockdown partially alleviated the LDH inhibition‐induced G1/S arrest. Furthermore, metabolic stress was accompanied by activation of p53‐mediated signaling, characterized by elevated γH2AX, p53, p21, and p38 levels. Silencing TP53 attenuated GADD45A induction and partially restored proliferative markers. Collectively, our findings support a model in which restricted lactate metabolism is associated with impaired goat primary GC proliferation, potentially through a coordinated mechanism involving H4K12la‐mediated epigenetic remodeling and p53‐associated stress signaling, both converging on GADD45A and contributing to early follicular degeneration.