Tetramethylpyrazine Targets HDAC6-Mediated PINK1 Degradation to Alleviate Chronic Intermittent Hypoxia-Induced Injury in Human Bronchial Epithelial Cells (16HBE)

Obstructive sleep apnea (OSA) is characterized by recurrent chronic intermittent hypoxia (CIH), which induces oxidative stress, inflammatory responses, and mitochondrial damage in bronchial epithelial cells. Tetramethylpyrazine (TMP) has been shown to exert lung-protective effects in Other pathological models, but its role in mitigating CIH-induced 16HBE cell injury and the underlying molecular mechanisms have not been previously investigated. PTEN-induced putative kinase 1 (PINK1)-mediated Mitophagy is a critical endogenous mechanism that defends against CIH-induced epithelial damage. However, whether TMP alleviates CIH-induced injury by regulating the PINK1 pathway remains unknown. CIH significantly reduced 16HBE cell viability, increased Apoptosis rate, elevated inflammatory responses (IL-6 and TNF-α levels upregulated), and oxidative stress (ROS and MDA levels increased), and inhibited Mitophagy (reduced PINK1 and LC3-II/LC3-I ratio, increased p62). TMP treatment improved cell viability in a dose-dependent manner; notably, 20 μg/mL TMP reversed CIH-induced Apoptosis, inflammation, and oxidative stress, accompanied by upregulated PINK1 and restored Mitophagy. Moreover, HDAC6 knockdown mimicked TMP's benefits (enhanced PINK1 and Mitophagy, reduced injury), while concurrent PINK1 silencing reversed this effect. TMP protected 16HBE cells from CIH-induced injury by inhibiting HDAC6-mediated PINK1 deacetylation. This mechanism stabilized PINK1 protein, enhanced Mitophagy, and thereby suppressed Apoptosis, oxidative stress, and inflammation, identifying the HDAC6/PINK1 axis as a key regulatory pathway in CIH-induced cell injury.

PTEN‐induced putative kinase 1; chronic intermittent hypoxia; deacetylation; histone deacetylase 6; mitochondrial damage; obstructive sleep apnea; tetramethylpyrazine.