Background: Sorafenib can improve the survival of metastatic clear cell renal cell carcinoma (ccRCC) patients. However, its benefits are modest, as patients eventually become resistant, and the mechanisms remain elusive. NUPR1, a stress-induced protein, has been reported in malignancies and functions as an oncogene by modulating the stress response, facilitating survival in harsh environments and conferring drug resistance. However, its role in ccRCC has not been explored.

Methods: The expression and clinical significance of NUPR1 were analyzed in ccRCC patients in in-house patients and The Cancer Genome Atlas (TCGA) cohorts. The biological functions of NUPR1 were investigated. Xenografts were performed to confirm the effects of NUPR1 on tumorigenesis. The molecular mechanism of NUPR1 was investigated in vitro and in vivo.

Results: NUPR1 expression was upregulated in tumor tissue. Further analysis showed that NUPR1 overexpression was associated with an aggressive phenotype and predicted a poor prognosis. Depletion of NUPR1 suppressed tumorigenesis and sensitized cells to sorafenib treatment. Finally, mechanistic investigations indicated that NUPR1 promoted tumorigenesis in ccRCC by increasing stemness and activating the PTEN/AKT/mTOR signaling pathway.

Conclusions: Collectively, our results suggest that NUPR1 may serve as a predictor of ccRCC. Notably, NUPR1 silencing reversed sorafenib resistance in ccRCC. These findings provide a novel potential therapeutic target in the clinical management of ccRCC.