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NSUN2 restrains renal fibrosis via m5C-stabilized GPX4 and ferroptosis inhibition
Yuxin Zan1, Lin Chen2, Liming Ma3
1Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.
Background:
Renal fibrosis (RFib) is a final common pathway in chronic kidney disease (CKD) progression. Although 5-methylcytosine (m5C) RNA modification can regulate mRNA fate, its role in RFib and redox-regulated cell death remains incompletely defined.
Methods:
Public GEO cohorts were analyzed to identify dysregulated m5C regulators and enriched pathways in RFib. RFib was modeled in vivo using unilateral ureteral obstruction (UUO) and in vitro using TGF-β1-treated HK-2 cells. Gene set enrichment analysis (GSEA) and a ferroptosis-focused qPCR array were used to prioritize downstream programs. NSUN2 knockdown/overexpression experiments, dot blot assays, and m5C RNA immunoprecipitation followed by qPCR (MeRIP-qPCR) were performed to evaluate m5C-associated regulation of GPX4. Network pharmacology and in silico docking/dynamics were used to nominate candidate NSUN2-binding compounds.
Results:
NSUN2 was consistently downregulated in fibrotic kidneys and TGF-β1-stimulated HK-2 cells, accompanied by ferroptosis activation. NSUN2 increased GPX4 protein abundance primarily by enhancing GPX4 mRNA stability, which correlated with increased m5C enrichment on GPX4 mRNA. Computational screening suggested that ginsenosides, particularly Rh2, may bind the NSUN2 catalytic pocket with favorable predicted affinity and complex stability.
Conclusions:
NSUN2 attenuates renal fibrogenesis by sustaining GPX4 expression through m5C-associated post-transcriptional regulation and thereby limiting ferroptosis. The identified ginsenosides provide testable leads for targeting the NSUN2-GPX4 axis, although further experimental validation is required.
Insights
The study shows that NSUN2, a regulator of RNA modification, protects against renal fibrosis by stabilizing GPX4 mRNA, thus inhibiting ferroptosis. This identifies a new therapeutic target for kidney disease.
Area of Science:
- Molecular Biology
- Renal Pathophysiology
- Epigenetics
Background:
- Renal fibrosis (RFib) is a key factor in chronic kidney disease (CKD) progression.
- The role of 5-methylcytosine (m5C) RNA modification in RFib and ferroptosis is not fully understood.
Purpose of the Study:
- To investigate the role of m5C regulators in renal fibrosis.
- To explore the connection between NSUN2, GPX4, and ferroptosis in RFib.
Main Methods:
- Analysis of public GEO cohorts and in vivo/in vitro RFib models.
- Gene set enrichment analysis (GSEA), qPCR arrays, and m5C RNA immunoprecipitation (MeRIP-qPCR).
- Network pharmacology and in silico studies to identify potential therapeutic compounds.
Main Results:
- NSUN2 was downregulated in fibrotic kidneys and HK-2 cells, correlating with ferroptosis activation.
- NSUN2 enhanced GPX4 protein by increasing GPX4 mRNA stability via m5C modification.
- Ginsenosides, particularly Rh2, were computationally identified as potential NSUN2 binders.
Conclusions:
- NSUN2 mitigates renal fibrogenesis by maintaining GPX4 expression through m5C-mediated post-transcriptional regulation, thereby limiting ferroptosis.
- Targeting the NSUN2-GPX4 axis with identified ginsenosides shows therapeutic potential for RFib, requiring further validation.
