CHCHD2 drives alcohol-Induced EMT via Bcl-2/ROS/p38 MAPK in Hypopharyngeal SCC

Hypopharyngeal squamous cell carcinoma (HPSCC), one of the most aggressive malignancies in the upper aerodigestive tract, is characterized by poor prognosis and low overall survival rates. While alcohol consumption constitutes a key risk factor driving its progression, the molecular mechanisms underlying HPSCC adaptation to alcohol-induced oxidative stress remain unclear. This study elucidates the role of CHCHD2 in mediating alcohol-driven epithelial-mesenchymal transition (EMT) through regulation of the Bcl-2/ROS/p38 MAPK signaling axis. Pan-cancer bioinformatics analysis revealed CHCHD2 overexpression across multiple cancers associated with unfavorable prognosis. Experimental validation via qPCR and Western blot confirmed elevated CHCHD2 levels in HPSCC tumor tissues and cell lines, with high-intensity alcohol exposure further upregulating CHCHD2 expression in FaDu cells. Functional studies demonstrated that CHCHD2 overexpression promotes Bcl-2 expression, reduces reactive oxygen species (ROS) levels, and activates p38 MAPK signaling, thereby driving cell proliferation, migration, and EMT progression. Conversely, CHCHD2 knockdown effectively suppressed alcohol-induced EMT phenotypes. These findings establish CHCHD2 as a critical alcohol-stress responsive molecule that facilitates HPSCC progression via the Bcl-2/ROS/p38 MAPK axis, providing a theoretical foundation for developing CHCHD2-targeted therapeutic interventions.