Increased ZNF83 is a potential prognostic biomarker and regulates oxidative stress-induced ferroptosis in clear cell renal cell carcinoma.

While zinc finger proteins (ZFPs) are known to be crucial in various cellular activities such as gene expression regulation and energy metabolism, their specific roles in tumor progression are not well-documented. This study focuses on Zinc Finger Protein 83 (ZNF83) to explore its impact on clear cell renal cell carcinoma (ccRCC) and assess its viability as a prognostic biomarker. Public datasets were utilized to analyze ZNF83's expression and functions in ccRCC systematically. Further, in vitro and in vivo experiments were conducted to delve deeper into ZNF83's functional role. Techniques like electron microscopy for mitochondrial morphology and ROS level quantification were used to assess ferroptosis. RNA sequencing and metabolomic mass spectrometry were employed to understand ZNF83's role in oxidative stress modulation and ferroptosis resistance. Our findings demonstrated that ZNF83 overexpression significantly enhanced tumor cell survival and proliferation, while ZNF83 knockout suppressed these processes. Under oxidative stress or upon treatment with ferroptosis inducers, ZNF83 expression was markedly upregulated, and the protein predominantly localized to the cell nucleus. Notably, ZNF83 overexpression conferred resistance to ferroptosis, promoting tumor cell survival under ferroptosis-inducing conditions. Conversely, ZNF83 knockout sensitized cells to ferroptosis, increasing tumor cell death. RNA-seq and metabolomic analyses revealed that ZNF83 is intricately involved in the regulation of NRF2, a master regulator of the antioxidant response, and associated signaling pathways. ZNF83 represents a key ferroptosis regulator in ccRCC, serving as both a promising prognostic biomarker and therapeutic target. Targeting ZNF83 may improve treatment strategies for ccRCC patients. KEY MESSAGES: ZNF83 as a crucial regulator of tumor cell survival and proliferation in renal cancer, a novel discovery in the context of renal cancer progression. ZNF83 overexpression confers resistance to ferroptosis, enhancing tumor cell survival under oxidative stress or ferroptosis-inducing conditions. Utilizing both RNA sequencing and metabolomic mass spectrometry, we provide comprehensive insights into the molecular pathways, particularly NRF2-related, regulated by ZNF83 in ccRCC. ZNF83's potential as a novel prognostic biomarker for ccRCC is proposed, offering a new avenue for personalized treatment strategies and improving treatment outcomes for patients.