CCPG1-mediated reticulophagy promotes tumorigenesis and cisplatin resistance in bladder cancer

Reticulophagy, a selective macroautophagy/autophagy process targeting endoplasmic reticulum fragments <i>via</i> receptors, plays a critical role in cellular homeostasis. This study reveals that CCPG1, a reticulophagy receptor, drives bladder cancer (BLCA) tumorigenesis and confers cisplatin resistance. We observed elevated reticulophagy activity in BLCA cells compared to normal counterparts, particularly under conditions of nutrient stress. <i>CCPG1</i> expression was significantly upregulated in BLCA patient samples and correlated with poor prognosis. Functional studies demonstrated that <i>CCPG1</i> knockdown suppressed reticulophagy, leading to decreased cell proliferation and increased apoptosis. Conversely, overexpression of the wild-type <i>CCPG1</i>, but not a MAP1LC3/LC3-binding-deficient variant, rescued reticulophagy and promoted tumor growth. Notably, we found that cisplatin treatment inhibited reticulophagy by downregulating <i>CCPG1</i> expression through the ATM-CHEK2/Chk2 signaling pathway. <i>CCPG1</i> knockdown synergistically enhanced cisplatin cytotoxicity to BLCA cells, while <i>CCPG1</i> overexpression conferred resistance. These findings highlight CCPG1-mediated reticulophagy as a driver of BLCA progression and as a potential prognostic biomarker and therapeutic target.