Abstract

Perioperative neurocognitive disorders (PND) are common complications in elderly surgical patients, yet the molecular mechanisms underlying this condition remain poorly understood. Accumulating evidence suggests that HDAC7—a member of the class IIa histone deacetylase (HDAC) family—plays a crucial role in brain injury and can activate the NF-κB pathway independently of its deacetylase activity. In the present study, we investigated whether upregulation of hippocampal HDAC7 contributes to PND through NF-κB–mediated mitochondrial dysfunction and ferroptosis. A tibial fracture model was established in 18-month-old mice, and elevated levels of HDAC7 and phosphorylated NF-κB (P-NF-κB) were detected in the hippocampal CA3 region 3 days after surgery. Moreover, bilateral injections of HDAC7 AAV-shRNA into the CA3 region reduced P-NF-κB levels and alleviated mitochondrial damage. HDAC7 knockdown restored mitofusin 2 (MFN2) expression, reversed the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4) and the loss of glutathione peroxidase 4 (GPX4), normalized the levels of ferroptosis-related markers (Fe 2+ , MDA, GSH, and SOD), and improved cognitive performance. In vitro, HT22 neurons exposed to conditioned medium from lipopolysaccharide (LPS)-activated BV2 microglia underwent ferroptotic cell death, which was prevented by ferrostatin-1 but not by apoptosis or autophagy inhibitors. Notably, pharmacological inhibition of the enzymatic activity of class IIa HDACs with TMP269 failed to attenuate ferroptosis, whereas HDAC7 knockdown suppressed P-NF-κB activation, restored MFN2 expression, corrected ACSL4/GPX4 abnormalities, and suppressed ferroptosis, further supporting a deacetylase-independent role of HDAC7. Furthermore, treatment with MASM7, an MFN2 activator, alleviated ferroptosis in vitro without affecting HDAC7 expression or NF-κB phosphorylation. In vivo, MASM7 administration also improved cognitive function and mitigated ferroptosis-related changes