J Biol Chem. 2026 Mar 23:111388. doi: 10.1016/j.jbc.2026.111388. Online ahead of print.
ABSTRACT
Obstructive sleep apnea (OSA) induces childhood cognitive impairment via chronic intermittent hypoxia (CIH), a process to which endoplasmic reticulum stress (ERS)-mediated apoptosis critically contributes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is widely recognized for its significant neuroprotective effects in various neurological diseases, yet its role in ERS-related apoptosis in prefrontal neurons under CIH remains unclear. This study investigated Nrf2's impact both in vitro and in vivo. In CIH-exposed Pheochromocytoma 12 (PC12) cells, mimicking OSA-related neuronal injury, CIH significantly triggered ERS and subsequent apoptosis, evidenced by the upregulated protein levels of ERS markers (p-PERK, ATF4, CHOP) and apoptotic markers (Cleaved-Caspase-3). Additionally, the antioxidant system was activated, as shown by elevated mRNA/protein levels of Nrf2, HO-1, and Gclc. Treatment with the Nrf2 activator sulforaphane (SFN) reduced CIH-induced apoptosis by suppressing ERS signaling and enhancing HO-1 mRNA/protein expression. Conversely, ML385 (a Nrf2 inhibitor) resulted in opposite outcomes. In vivo, after 4 weeks of CIH exposure, mice demonstrated spatial memory and learning deficits in the behavior test. In the prefrontal cortex, histological examination revealed increased neuronal apoptosis, characterized by elevated Cleaved-Caspase-3 protein levels, alongside activation of the Nrf2 pathway. Treatment with SFN alleviated cognitive impairment and neuronal apoptosis by inhibiting ERS signaling, while enhancing HO-1 mRNA/protein expression. Conversely, treatment with a Nrf2 inhibitor had the opposite effects. In summary, we demonstrate that Nrf2 mitigates CIH-induced neuronal apoptosis by suppressing the PERK-ATF4-CHOP signaling cascade and augmenting HO-1 expression, thereby improving cognitive impairment.
PMID:41881261 | DOI:10.1016/j.jbc.2026.111388