ERK- and p53-Mediated ATF3 Expression Contributes to Cisplatin-Induced DNA Damage in Renal Epithelial Cells

Semin Lee^1,2,#, Minjun Kim^3,4,#, Seungmin Lee^2,5, Jiyun Yoo^1,5, Soo Seok Hwang^6,7, Seongchan Kim⁸, Seung Pil Yun^9,10, Dong Kyu Choi^11,12,*, Sangdun Choi^13,14,*, Hyuk-Kwon Kwon^1,2,5,*
1 Division of Applied Life Science, Gyeongsang National University, Jinju, Republic of Korea
2 Division of Bio & Medical Bigdata Department (BK4 Program), Gyeongsang National University, Jinju, Republic of Korea
3 Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA
4 Research Institute of Life Sciences, Gyeongsang National University, Jinju, Republic of Korea
5 Division of Life Science, Gyeongsang National University, Jinju, Republic of Korea
6 School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
7 Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea
8 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea
9 Department of Pharmacology, Institute of Medical Sciences, College of Medicine, Gyeongsang National University, Jinju, Republic of Korea
10 Department of Convergence Medical Science, College of Medicine, Gyeongsang National University, Jinju, Republic of Korea
11 KNU G-LAMP Project Group, KNU Institute of Basic Sciences, Kyungpook National University, Daegu, Republic of Korea
12 BK21 FOUR KNU Creative BioResearch Group, School of Life Science and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
13 S&K Therapeutics, Ajou University, Suwon, Republic of Korea
14 Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
* Corresponding Author: Dong Kyu Choi. Email: email ; Sangdun Choi. Email: email ; Hyuk-Kwon Kwon. Email: email
# These authors contributed equally to this work

BIOCELL https://doi.org/10.32604/biocell.2026.074555

Received 13 October 2025; Accepted 19 January 2026; Published online 05 February 2026

Abstract

Objective: Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer. However, its clinical application is often limited by adverse effects on normal tissues, especially the kidneys. Understanding the molecular mechanisms of cisplatin-induced nephrotoxicity is crucial for developing strategies to mitigate its side effects. In this study, we aimed to elucidate the molecular mechanisms underlying cisplatin-induced DNA damage and apoptosis in human renal epithelial cells, with a focus on key signaling pathways and mediators that drive nephrotoxicity. Methods: To explore these mechanisms, human proximal tubule epithelial cells (HK-2) were treated with cisplatin. The study assessed DNA damage response (DDR) and stress-related protein expression, cell cycle distribution, and apoptosis. Activation of mitogen-activated protein kinases (MAPKs), particularly Extracellular signal-regulated Kinase (ERK), was analyzed, along with the expression and functional role of activating transcription factor 3 (ATF3) and tumor protein p53 (p53). Results: Cisplatin treatment upregulated DDR and stress response proteins, induced S phase arrest, and increased the SubG1 population, indicating apoptotic cell death. ERK was identified as a critical mediator of cisplatin-induced DNA damage and stress responses. ATF3 expression was significantly elevated in an ERK-dependent manner and required p53 activation. Knockdown of ATF3 reduced cisplatin-induced DNA damage, highlighting its role in the cytotoxic response. Conclusions: Cisplatin induces nephrotoxicity through ERK- and p53-dependent upregulation of ATF3, which is associated with DNA damage and cell death, suggesting a modulatory role in the cellular stress response. These findings provide novel insights into the molecular basis of cisplatin-induced renal injury and suggest potential therapeutic targets to alleviate its adverse effects.