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

Summary

In an aged-mouse tibial fracture model, hippocampal HDAC7 and phosphorylated NF-κB increased 3 days post-surgery. AAV-shRNA knockdown of HDAC7 reduced NF-κB activation, ameliorated mitochondrial injury, restored MFN2, reversed ACSL4 upregulation and GPX4 loss, and normalized ferroptosis markers, implicating an HDAC7–NF-κB–MFN2–ACSL4 ferroptosis pathway in perioperative neurocognitive disorders.

Key Findings

• Surgery in aged mice increased hippocampal HDAC7 and phosphorylated NF-κB in CA3 at day 3.
• HDAC7 knockdown via AAV-shRNA reduced NF-κB activation, alleviated mitochondrial injury, and restored MFN2.
• Ferroptosis signatures (ACSL4 up, GPX4 loss, related markers) were reversed by HDAC7 knockdown, implicating an NF-κB–MFN2–ACSL4 pathway.

Clinical Implications

Although preclinical, the data support exploring HDAC7 inhibition and ferroptosis-targeted therapies (e.g., ACSL4 inhibition, GPX4 preservation) to prevent postoperative cognitive decline in older adults.

Limitations

• Preclinical mouse model limits direct clinical generalizability
• Behavioral and long-term cognitive outcomes are not detailed in the abstract

Future Directions

Translate findings to human biomarker studies of ferroptosis in PND and test HDAC7/ferroptosis inhibitors in perioperative prevention trials.