KCNK5 encodes a two-pore domain potassium channel that conducts voltage-dependent outward rectifying currents through an 'ion flux gating' mechanism where outward potassium flow opens the channel gate 123. The channel homo- and heterodimerizes to form functional channels with distinct regulatory properties 2. KCNK5 is transcriptionally regulated by hypoxia through oxygen-sensitive promoter elements 4 and functions in excitability, volume regulation, and bicarbonate handling across tissues 4. In pathological contexts, KCNK5 exhibits contrasting roles. During ischemic stroke, KCNK5 is upregulated on neurons and promotes apoptosis; KCNK5 knockout mice demonstrated reduced infarct volumes and improved neurologic outcomes, suggesting the channel exerts pro-apoptotic effects under ischemia 5. Conversely, rare variants with cis-regulatory effects on KCNK5 confer protection against migraine and brain aneurysms 6. KCNK5 has been identified as a druggable therapeutic target for migraine through genome-wide Mendelian randomization analyses 78. In dry eye disease, KCNK5 upregulation mediates potassium efflux, activating NLRP3 inflammasome-mediated pyroptosis through TNFSF10-regulated autophagy impairment; KCNK5 silencing mitigated pyroptosis 9. Additionally, KCNK5 variants have been associated with regulation of platelet maturity indices 10, and exome sequencing identified KCNK5 mutations in Balkan endemic nephropathy patients 11.