Neuroprotective role of NRF2 activation against ER Stress-Mediated apoptosis in obstructive sleep apnea.

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 levels of Nrf2, Hmox1, and Gclc and 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 Hmox1 mRNA and HO‑1 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 Hmox1 mRNA and HO‑1 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.