Histone H4K16 acetylation modification regulated autophagy and apoptosis in neuron after spinal cord injury

Autophagy maintains the homeostasis of the internal environment by clearing misfolded proteins and damaged organelles, which can reduce neuronal apoptosis in the early stage of spinal cord injury (SCI) and promote neural function recovery. Previous studies have shown that decreased acetylation modification of histone H4 lysine16 acetylation (H4K16ac) induces the expression of downstream autophagy genes. However, the role of H4K16ac modification and its impact on autophagy and apoptosis in the early stage of SCI remains unclear. This study aimed to determine the relationship between H4K16ac and autophagy, apoptosis in the early stage of SCI, and the effects of regulating H4K16ac on autophagy and apoptosis. In this study, the state of nerve cells after spinal cord injury was simulated by the rat pheochromocytoma cell line (PC12 cells) injured by oxygen-glucose deprivation (OGD) Model. Using OGD model in NGF-differentiated PC12 cells, we assessed H4K16ac dynamics via Western blot, immunofluorescence, and qPCR. Autophagy and apoptosis were evaluated through transmission electron microscopy, LC3B/p62 analysis, TUNEL staining, and flow cytometry. Results showed that OGD reduced H4K16ac in a time-dependent manner, correlating with enhanced autophagy (increased LC3B-II/I, Beclin1, ATG5; decreased p62) and apoptosis (elevated Bax/Bcl-2, cleaved caspase-3). Pharmacological inhibition of deacetylases by Trichostatin A (TSA) restored H4K16ac, suppressed autophagy, and exacerbated apoptosis. Similarly, Sirtuin 1 (SIRT1) knockdown upregulated H4K16ac, inhibited autophagic flux, and promoted apoptosis via the Bax/Bcl-2/caspase-3 pathway. These findings reveal that H4K16ac downregulation post-SCI enhances autophagy as a protective response, while its restoration via SIRT1 inhibition disrupts this balance, aggravating neuronal apoptosis.