CLIC1, or Chloride intracellular channel 1, is a protein that exists as either a monomeric soluble protein or a non-covalent dimeric protein capable of forming an ion channel. It is involved in multiple biological processes. It promotes cell cycle progression, cancer stem cell (CSC) self-renewal, and plays roles in proliferation, cell volume regulation, tumour invasion, migration, and angiogenesis [1]. It is also associated with pathways like Wnt/β-catenin/TCF4 signaling, ROS/HIF1α signaling, and is involved in the regulation of redox state, calcium homeostasis, and the Nrf2/HO-1 pathway [1,2,6,7].

In glioblastoma, CLIC1 facilitates the G1/S phase transition and regulates glioma stem-like cells (GSCs), which are crucial for tumour resistance and recurrence. Inhibiting CLIC1 in glioma cells leads to apoptosis and reduced cell motility [1,4]. In pancreatic cancer, elevated CLIC1 expression, induced by matrix stiffness, promotes glycolytic metabolism and tumour proliferation [2]. In hepatocellular carcinoma, CLIC1 drives angiogenesis by modulating VEGFA, and its high expression is associated with poor prognosis [3]. In oral squamous cell carcinoma, higher CLIC1 plasma concentration is associated with lymph node metastases [5]. In esophageal cancer, KCTD4 binds to CLIC1, disrupts its dimerization, increases intracellular Ca2+ levels, and promotes metastasis [7]. In endothelial cells, inhibiting CLIC1 protects against cellular senescence and endothelial dysfunction via the Nrf2/HO-1 pathway [6]. In obesity models, Clic1 knockout mice ate less and had lower body weight, and pharmacological inhibition of Clic1 also reduced food intake and promoted weight loss [8].

In conclusion, CLIC1 is a multi-functional protein involved in various biological processes and diseases. Studies using gene knockout or knockdown models in different disease contexts have revealed its roles in cancer progression, angiogenesis, metastasis, endothelial function, and obesity. These findings suggest that CLIC1 could be a potential therapeutic target for treating these diseases.