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

Abstract

ABSTRACT 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.