Hippocampal HDAC7 induces perioperative neurocognitive disorders via an NF-κB-MFN2-ACSL4 ferroptosis pathway

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 (Fe²⁺, 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 after surgery. Taken together, these findings demonstrate that HDAC7 promotes neuronal ferroptosis through the NF-κB-MFN2-ACSL4 pathway, thereby contributing to the development of PND.