CSRNP1 Promotes Apoptosis and Mitochondrial Dysfunction via ROS-Mediated JNK/p38 MAPK Pathway Activation in Hepatocellular Carcinoma
Huihui Shi1,#, Lei Chen2,#, Juan Huang3,#, Xuejing Lin2, Lei Huang4, Min Tang4, Kai Lu5,*, Wenchao Wang4,*, Maoling Zhu1,§,*
1 Department of Gastroenterology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
2 Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
3 Department of Surgical Room, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
4 Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
5 Department of Hepatic-Biliary-Pancreatic Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
* Corresponding Author: Kai Lu. Email: 
; Wenchao Wang. Email: 
; Maoling Zhu. Email: 
# These authors contributed equally to this work
(This article belongs to the Special Issue: Molecular Targets and Combinatorial Therapeutics of Liver Cancer)
Oncology Research https://doi.org/10.32604/or.2025.068737
Received 05 June 2025; Accepted 03 September 2025; Published online 09 October 2025
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis.
Methods: Differential expression analyses were performed across three datasets—The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698—to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 (
CSRNP1) expression levels in HCC cell lines were assessed via western blot (WB) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of
CSRNP1 knockdown or overexpression on cell proliferation, migration, and apoptosis were evaluated using cell counting-8 (CCK-8) assays, Transwell assays, and flow cytometry. Mitochondrial ultrastructure was examined by transmission electron microscopy, and intracellular and mitochondrial reactive oxygen species (mROS) levels were measured using specific fluorescent probes. WB was used to assess activation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and pathway dependence was examined using the ROS scavenger N-Acetylcysteine (NAC) and the JNK inhibitor SP600125.
Results: A six-gene prognostic model was established, comprising downregulated genes (
NR4A1 and
CSRNP1) and upregulated genes (
CENPQ,
YAE1,
FANCF, and
POC5) in HCC. Functional experiments revealed that
CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis. Conversely,
CSRNP1 overexpression impaired mitochondrial integrity, increased both mitochondrial and cytoplasmic ROS levels, and activated the JNK/p38 MAPK pathway. Notably, treatment with NAC or SP600125 attenuated
CSRNP1-induced MAPK activation and apoptosis.
Conclusion: CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC. It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner. These findings suggest that
CSRNP1 may serve as a potential therapeutic target in the management of HCC.
Graphical Abstract
Keywords
Cysteine/serine-rich nuclear protein 1; c-Jun N-terminal kinase/p38 mitogen-activated protein kinase pathway; hepatocellular carcinoma; reactive oxygen species accumulation; mitochondrial dysfunction
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