SIRT7-Mediated H2BK120 Succinylation Drives Aberrant Mitophagy in Sepsis-Associated Cognitive Dysfunction

Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, yet how metabolic disturbances engage epigenetic regulation in SAE remains unclear. We found that septic mice exhibited hippocampal succinate and succinyl-CoA accumulation, accompanied by enhanced neuronal histone H2BK120 succinylation (H2BK120su). Pharmacological reduction of succinylation alleviated neuronal injury and improved cognitive function. Mechanistically, integrated CUT&Tag and transcriptomic analyses identified Pdcd1 as a downstream gene associated with H2BK120su enrichment. H2BK120su enrichment at the Pdcd1 promoter activated the PD-1/PD-L1 axis, promoted mitochondrial translocation of PD-L1 and its interaction with PINK1, and triggered PINK1/Parkin-dependent mitophagy, leading to mitochondrial dysfunction and neuronal apoptosis. Neutralization of PD-1/PD-L1 or knockdown of Pdcd1 attenuated mitophagy and neuronal injury. We further identified SIRT7 downregulation as a major cause of H2BK120su accumulation in the septic hippocampus. Neuron-specific Sirt7 deletion exacerbated H2BK120su enrichment, PD-1/PD-L1 activation, excessive mitophagy, and cognitive impairment, whereas SIRT7 overexpression reversed these pathological changes. Together, our findings define a SIRT7-H2BK120su-PD-1/PD-L1-PINK1 axis linking metabolic reprogramming to aberrant mitophagy in SAE and suggest SIRT7-dependent succinylation as a potential therapeutic target.