PABPC1-induced stabilization of PGK1 mRNA reduces apoptosis and sunitinib sensitivity in renal cell carcinoma by suppressing endoplasmic reticulum stress.

Sunitinib resistance poses a significant challenge in the management of advanced and metastatic clear cell renal cell carcinoma (ccRCC). Although RNA-binding proteins (RBPs) have recently emerged as important regulators of tumorigenesis, their roles in ccRCC progression and sunitinib resistance remain poorly understood. Through comprehensive bioinformatics analysis of clinical datasets, we identified PABPC1 as an RBP significantly upregulated in ccRCC. Functionally, PABPC1 promoted the proliferation, migration, invasion, and sunitinib resistance of ccRCC cells. Mechanistically, PABPC1 bound to and stabilized PGK1 mRNA, thereby upregulating PGK1 expression. This upregulation reduced endoplasmic reticulum (ER) stress, inhibited apoptosis, and consequently conferred sunitinib resistance in ccRCC cells. Importantly, treatment with Eeyarestatin I, a small-molecule ER stress agonist, restored sunitinib sensitivity in tumor cells. These findings reveal a novel PABPC1-PGK1 regulatory axis underlying sunitinib resistance and suggest a promising therapeutic strategy for overcoming drug resistance in ccRCC.