TJP2 (tight junction protein 2) is a scaffold protein essential for establishing and maintaining hepatic tight junctions and bile canalicular structure. TJP2 localizes to cell-cell junctions where it regulates membrane permeability and coordinates the distribution of apical transporters, including the bile salt export pump (BSEP) 1. The protein functions through multivalent interactions within its PDZ-SH3-GuK domain to organize junction assembly via phase separation, enabling proper clustering and localization of adhesion receptors and transporters 2. Loss-of-function mutations in TJP2 cause progressive familial intrahepatic cholestasis (PFIC), characterized by impaired bile acid transport, hepatocellular injury, and progressive cirrhosis 3. In TJP2-deficient hepatocytes, loss of normal canalicular architecture, reduced claudin-1 protein levels, and mislocalization of key bile transporters result in compromised directional bile acid transport and cholestasis 41. Disease severity correlates with mutation type: patients with protein-truncating mutations on both alleles experience early infantile cholestasis with rapid progression to liver failure or death without transplantation 5. Maralixibat, an ileal bile acid transporter inhibitor, provides symptomatic improvement in PFIC patients including those with TJP2 deficiency, reducing pruritus and bile acid levels 6.