Molecular Role of CLIC1 in Oral Cancer: From Ion Channel Dynamics to Tumorigenesis

Abstract

Oral squamous cell carcinoma (OSCC) remains a globally prevalent malignancy with limited effective biomarkers and molecular targets for early detection and therapy. The chloride intracellular channel 1 (CLIC1), a redox-sensitive protein with dual localization in cytosolic and membrane-bound forms, has emerged as a key regulator of ion homeostasis and tumorigenesis. CLIC1 translocates from cytosol to the plasma membrane under oxidative conditions, modulating chloride flux and influencing intracellular ROS balance, which in turn affects cell survival and proliferation. Functionally, CLIC1 overexpression in OSCC correlates with enhanced cell proliferation, invasion, angiogenesis, and lymphatic metastasis, whereas its inhibition promotes apoptosis and chemosensitivity. Mechanistically, CLIC1 interacts with oncogenic signaling pathways, including NF-κB, PI3K/Akt, and p53, creating a feedback loop where ROS-mediated redox shifts drive ERK/MAPK activation and integrin signaling. Network pharmacology and protein–protein interaction analyses reveal that the CLIC1 interactome converges on genes governing cell cycle control, epithelial–mesenchymal transition, and mitochondrial metabolism, linking its channel dynamics to aggressive tumor phenotypes. Given its consistent overexpression across tumor grades and its association with poor prognosis, CLIC1 represents a promising theranostic candidate in OSCC. Targeting its redox-regulated ion channel function or downstream effectors may offer new strategies for precision intervention and biomarker-driven therapy in oral cancer management.​