KLF4 is Associated with Perioperative Neurocognitive Disorder and SMAD7-linked Oxidative Stress and Ferroptosis-Related Signaling

Perioperative neurocognitive disorder (PND) is a common complication after anesthesia and surgery, particularly in older individuals, and is associated with oxidative stress and ferroptosis. Krüppel-like factor 4 (KLF4) has been implicated in neuronal injury, but its role in PND remains unclear. Using a mouse model of sevoflurane anesthesia plus tibial fracture surgery and sevoflurane-exposed HT22 cells, we found that KLF4 was upregulated in the hippocampus after anesthesia and surgery, as well as in HT22 cells. KLF4 knockdown alleviated cognitive impairment and neuronal injury in vivo and improved cell viability while reducing apoptosis in vitro. Mechanistically, KLF4 depletion attenuated oxidative stress and ferroptosis-related changes, including reduced ROS, iron accumulation, MDA, LDH, and ACSL4 expression, together with restored GSH, antioxidant activity, GPX4, and SLC7A11 levels. Multiplex immunofluorescence showed that surgery-induced GPX4 loss and ACSL4 upregulation occurred predominantly in hippocampal neurons, whereas 4-HNE accumulation was observed in both neurons and microglia. KLF4 directly bound to the SMAD7 promoter and enhanced SMAD7 transcription. Rescue experiments showed that KLF4 overexpression reversed the protective effects of SMAD7 knockdown, and in the absence of sevoflurane, KLF4 overexpression alone induced toxicity that was only partially rescued by SMAD7 knockdown. Together, these findings suggest that KLF4 is associated with PND-related neuronal injury, potentially through SMAD7-linked oxidative stress and ferroptosis-related signaling.