CLIC3 (chloride intracellular channel 3) is a multifunctional protein with dual roles as both an ion channel and a glutathione-dependent oxidoreductase. In its soluble state, CLIC3 catalyzes thiol-disulfide exchange reactions and is secreted into the extracellular matrix where it activates transglutaminase-2 (TGM2) by reducing specific cysteines, promoting angiogenesis and blood vessel growth 1. CLIC3 can insert into membranes to form chloride ion channels regulating cellular chloride concentration and cell volume 2. CLIC3 drives cancer progression through multiple mechanisms: it regulates recycling of invasive cargo including α5β1 integrin and MT1-MMP from late endosomes to the plasma membrane, facilitating cancer cell invasion and metastasis 34. In bladder cancer, CLIC3 interacts with NAT10 to inhibit N4-acetylcytidine modification of p21 mRNA, reducing p21 expression and promoting proliferation 5. CLIC3 also mediates fibroblast cellular senescence through ERK7 interaction, regulating chloride homeostasis and mitochondrial function 6. Clinically, elevated CLIC3 expression correlates with poor prognosis in pancreatic, ovarian, and breast cancers 314. CLIC3 is increased in placental complications including fetal growth restriction and pre-eclampsia 2, and identified as a risk factor for proliferative diabetic retinopathy 7.