TFEB drives ER stress-induced apoptosis and limits cyst growth in polycystic kidney disease

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts and loss of renal function. Here, it was demonstrated that transcription factor EB (TFEB) activation in cyst-lining epithelial cells enhances their susceptibility to apoptosis via endoplasmic reticulum (ER) stress-induced signaling, ultimately restricting cyst expansion. Single-cell RNA sequencing in Pkd1 -deficient mouse models identified G-protein coupled receptor family C group 5 member A (GPRC5A)-positive cyst-lining cell clusters originating from the loop of Henle and proximal tubules. These cells exhibited dysregulated Hippo signaling and enhanced unfolded protein response (UPR). With this change in UPR, nuclear localization of TFEB and C/EBP homologous protein (CHOP) was observed, and expression of pro-apoptotic target genes of CHOP, such as Ppp1r15 and Pmaip1 , increased. TFEB deficiency attenuated apoptosis, resulting in accelerated cyst growth. Human ADPKD kidney samples mirrored these findings, showing nuclear TFEB and CHOP accumulation in cyst-lining cells. These results indicated that TFEB is a key modulator of ER stress-induced apoptosis in cyst-lining cells, suggesting that TFEB activation paradoxically limits cyst expansion through apoptosis in ADPKD.