nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression

Neuronal nitric oxide synthase (nNOS) plays dual roles in tumorigenesis, but its function in hepatoblastoma (HB) remains unclear. Analysis of 30 clinical HB samples reveals significant nNOS downregulation, correlating with tumor malignancy. Overexpression of nNOS inhibits HB cell proliferation and tumor growth in vitro and in vivo. Multi-omics analysis identifies the MAPK pathway as a key target, with KRAS protein levels most prominently reduced. Mechanistically, nNOS induces S-nitrosylation of TCOF1 at cysteine 644, disrupting TCOF1-KRAS interaction and thereby accelerating KRAS protein degradation. These findings establish the nNOS-TCOF1-KRAS axis as a critical regulator of HB progression and propose a novel NO-based therapeutic strategy for KRAS-driven cancers.

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Publication Details

Journal
Redox Biology
Published
2025-09-23
DOI
https://doi.org/10.1016/j.redox.2025.103870
Primary Topic
Nitric Oxide and Endothelin Effects
Type
article
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article

nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression

Ziyan Luo, Lin Qiu, Zhiyong Lin, Z.X. Li et al.
Redox Biology
Nitric Oxide and Endothelin Effects
article

nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression

Ziyan Luo, Lin Qiu, Zhiyong Lin, Z.X. Li, Linna Yu, Q. Yue, Meng Wang, Yupeng Wang, Lingling Wu, Hua Jiang, Siqi Dong, Fang Yu
article en

Abstract

Neuronal nitric oxide synthase (nNOS) plays dual roles in tumorigenesis, but its function in hepatoblastoma (HB) remains unclear. Analysis of 30 clinical HB samples reveals significant nNOS downregulation, correlating with tumor malignancy. Overexpression of nNOS inhibits HB cell proliferation and tumor growth in vitro and in vivo. Multi-omics analysis identifies the MAPK pathway as a key target, with KRAS protein levels most prominently reduced. Mechanistically, nNOS induces S-nitrosylation of TCOF1 at cysteine 644, disrupting TCOF1-KRAS interaction and thereby accelerating KRAS protein degradation. These findings establish the nNOS-TCOF1-KRAS axis as a critical regulator of HB progression and propose a novel NO-based therapeutic strategy for KRAS-driven cancers.

Redox BiologyVol. 87
Kunming University of Science and Technology (CN), First People's Hospital of Yunnan Province (CN), Guangzhou Women and Children Medical Center (CN), Guangdong Provincial Hospital of Traditional Chinese Medicine (CN), The First Hospital of Kunming (CN), Zhujiang Hospital (CN), Southern Medical University (CN), Guangzhou Medical University (CN)
Openalex Percentile: Top 67%
Nitric Oxide and Endothelin Effects
DOIOpen Access PDFOpenAlex
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nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression — Ziyan Luo, Lin Qiu, et al. · Redox Biology (2025) | TGRS Research Map | TGRS