Open Access
ARTICLE
PARP9 Modulates Sunitinib Resistance in Clear Cell Renal Cell Carcinoma via STAT1/IRF1 Signaling Pathway
Lei Luo1, Fengju Guan1, Zhankun Wang2, Bin Li1, Xuemei Ding1, Leilei Song1, Lijiang Sun1,*
1 Urological Department, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, China
2 Urological Department, Qingdao Eighth People’s Hospital, No. 84, Fengshan Road, Licang District, Qingdao, China
* Corresponding Author: Lijiang Sun. Email: 
(This article belongs to the Special Issue: Metabolic Heterogeneity in Cancer: Mechanisms, Biomarkers, and Therapeutic Implications)
Oncology Research https://doi.org/10.32604/or.2026.080621
Received 13 February 2026; Accepted 20 April 2026; Published online 11 May 2026
Abstract
Background: Resistance to sunitinib represents a major clinical obstacle in the management of clear cell renal cell carcinoma (ccRCC). This investigation aims to identify genes associated with sunitinib resistance and elucidate potential molecular pathways in ccRCC. Methods: To identify differentially expressed genes (DEGs) in sunitinib-resistant ccRCC cells and their parental cells, bioinformatic analysis was performed on the GSE216494 dataset. Protein-protein interaction (PPI) network and topological analyses pinpointed a hub gene. Sunitinib-resistant A498 and 786-O cell lines were employed for in vitro validation. Sunitinib sensitivity and cell proliferation were evaluated using functional assays, such as colony formation and Cell Counting Kit-8 (CCK-8). Protein interactions and signaling pathway activity are investigated using co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, and immunofluorescence. In resistant cells and patient-derived organoids (PDOs), the therapeutic potential of olaparib, either by itself or in conjunction with sunitinib, was assessed. Results: Sunitinib-resistant cells and patient tissues were shown to exhibit consistent upregulation of poly (ADP-ribose) polymerase 9 (PARP9). PARP9 knockdown sensitized resistant cells to sunitinib, suppressing proliferation. Conversely, its overexpression induced resistance in parental cells. Additionally, STAT1 and PARP9 interact to promote nuclear translocation and STAT1 phosphorylation. Activation of the STAT1/IRF1 axis further enhanced the expression of ISG15 and IFIT1. Olaparib treatment can increase sunitinib-resistant ccRCC cells. Olaparib can weaken the STAT1/IRF1 signaling pathway and prevent sunitinib-resistant ccRCC cells from proliferating. Importantly, combination treatment with olaparib and sunitinib showed superior antitumor efficacy in ccRCC PDOs. Conclusion: This study demonstrates that PARP9 promotes sunitinib resistance in ccRCC by activating the STAT1/IRF1 pathway and upregulating ISG15/IFIT1.
Keywords
Clear cell renal cell carcinoma; PARP9; STAT1/IRF1 signaling pathway; sunitinib resistance; ISG15
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