ArticleCell death & disease2025
N6-methyladenosine-mediated upregulation of MANF promotes ER stress resistance in renal cell carcinoma.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Beyond mBiomedicines · 2026Review
- Functional Role of ALKBH5 in Kidney Injury: Insights Into Mechanisms and Therapeutic Potential.Journal of cellular biochemistry · 2026Review
- The Role of NMedComm · 2026Review
- Epitranscriptomic Stability-Variable Extents of N1-Methyladenosine to N6-Methyladenosine Conversion Under Different Experimental Conditions.Biomolecules · 2026Article
- The N6-Methyladenosine RNA Demethylase AlkB Homolog 5 (ALKBH5) in Metabolic Diseases: Molecular Mechanisms and Pharmacological Implications-A Review.Biomolecules · 2026Review
- The role of the nervous system in the occurrence, development, and immune response of renal cell carcinoma.Frontiers in immunology · 2025Review
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Authors and funding
10 authors.
Funding
Abstract
Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.
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