Background and Objectives: Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse, leading to intermittent hypoxia, oxidative stress, and systemic inflammation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in cellular adaptation to hypoxia, whereas Netrin family members have emerged as regulators of inflammatory and endothelial responses. However, the roles of Netrin-1 and Netrin-4 in OSA-related intermittent hypoxia remain unclear. This study aimed to investigate circulating HIF-1α, Netrin-1, and Netrin-4 levels in patients with OSA and to evaluate their associations with disease severity and hypoxic burden. Materials and Methods: This study included 52 patients with newly diagnosed OSA and 26 healthy controls. Participants were classified as severe OSA, mild-moderate OSA, or control according to apnea–hypopnea index (AHI) values. All participants underwent overnight polysomnography. Serum HIF-1α, Netrin-1, and Netrin-4 levels were measured using ELISA. ROC curve analyses were performed to assess the ability of the investigated biomarkers to distinguish patients with OSA from controls. Correlation analyses evaluated associations between biomarkers and polysomnographic parameters, while multiple linear regression analyses adjusted for BMI, age, gender, CRP, and LDL levels were used to identify independent associations. Results: Serum HIF-1α, Netrin-1, and Netrin-4 levels differed significantly among the groups (p < 0.0001) and progressively increased from controls to mild-moderate and severe OSA groups. ROC curve analyses demonstrated excellent discriminative performance for HIF-1α (AUC = 0.9072) and Netrin-1 (AUC = 0.8928), while Netrin-4 also showed good discriminative ability (AUC = 0.8284). HIF-1α levels were positively correlated with both AHI, reflecting disease severity, and T90, reflecting nocturnal hypoxic burden (p < 0.0001). Similar positive correlations were observed between Netrin-1, Netrin-4, and both AHI and T90 (p < 0.0001). In multiple linear regression analyses, AHI remained independently associated with HIF-1α, Netrin-1, and Netrin-4 after adjustment for BMI, age, gender, CRP, and LDL levels (p < 0.0001). In contrast, BMI, age, gender, CRP, and LDL were not significantly associated with any of these biomarker levels in the adjusted models. Conclusions: Circulating HIF-1α, Netrin-1, and Netrin-4 levels are significantly elevated in patients with OSA and are positively associated with disease severity and hypoxic burden. The independent relationship between AHI and these biomarkers suggests that intermittent hypoxia may contribute to activation of HIF-1α–related and Netrin-associated pathways in OSA. These findings indicate that Netrin family members may have potential relevance as biomarkers of hypoxia-associated inflammatory and endothelial alterations in OSA.

Background and Objectives: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key innate immune complex, and its aberrant activation contributes to metabolic and neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with anti-inflammatory and metabolic regulatory functions, but its role in NLRP3 inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis remains unclear. The aim of this study was to investigate the effects of BDNF deficiency on LPS- and nigericin-induced NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in vivo, and to elucidate the involvement of NF-κB signaling, autophagy, and ESCRT-III-dependent plasma membrane repair in this process. Materials and Methods: In this in vivo study, male Bdnf ^+/+ and Bdnf ^+/− mice were subjected to lipopolysaccharide (LPS) plus nigericin-induced NLRP3 inflammasome activation. Serum and hippocampus, cortex, liver, epididymal adipose, and muscle tissues were collected 24 h after stimulation for analysis of inflammasome-related, autophagy-related, and membrane repair-related proteins by Western blotting and of serum BDNF, interleukin-1β (IL-1β), and interleukin-18 (IL-18) by ELISA. Results: Bdnf ^+/− mice displayed significantly reduced circulating BDNF levels and exhibited exaggerated LPS plus nigericin-induced increases in IL-1β and IL-18 compared with Bdnf ^+/+ mice. Across all tissues, BDNF deficiency enhanced NF-κB p65, NLRP3, active caspase-1 p20, and GSDMD expression, indicating amplified inflammasome activation and pyroptosis. Conversely, LC3B and SQSTM1/p62 levels were decreased, and VPS4A expression, a key component of the ESCRT-III membrane repair machinery, was suppressed in Bdnf ^+/− mice, suggesting impaired selective autophagy, autophagosome formation, and plasma membrane repair. Conclusions: Together, these findings indicate that BDNF restrains NLRP3 inflammasome activation and GSDMD-mediated pyroptosis through inhibition of NF-κB signaling and coordinated activation of autophagy and ESCRT-III-dependent membrane repair. BDNF thus emerges as an endogenous negative regulator of inflammasome activity and a potential therapeutic target for conditions characterized by aberrant NLRP3-driven inflammation.