Defective Ribosome Biogenesis Drives Tubular Senescence and Renal Fibrosis via IRBC-p53 Activation

The science

Original title

Defective Ribosome Biogenesis Drives Tubular Senescence and Renal Fibrosis via IRBC-p53 Activation.

Authors

Song K, Su H

Journal

Cells

Published

Oct 26, 2026

Study type

Study · in humans

PMID

42929860 ↗

DOI

10.3390/cells15201888 ↗

Abstract

Impaired ribosome biogenesis (RiBi) triggers the impaired ribosome biogenesis checkpoint (IRBC), a nucleolar stress pathway that stabilizes p53 and induces cellular senescence. Whether RiBi dysfunction directly drives renal interstitial fibrosis (RIF) remains unknown. Here, we combined human IgA nephropathy biopsies, murine fibrosis models, and cultured proximal tubular epithelial cells treated with the RNA polymerase I inhibitor CX5461, the p53 inhibitor pifithrin-α, siRNA-mediated POLR1A knockdown, and the DNA-damaging agent etoposide to dissect the RiBi-IRBC-p53-senescence axis. We identified defective rDNA transcription in the proximal tubules of fibrotic human kidneys and in experimental fibrosis models. Pharmacological RiBi inhibition with CX5461 induced RIF prior to functional decline. Mechanistically, RiBi impairment promoted RPL5/RPL11 binding to HDM2, stabilized p53, upregulated p21, and induced G2/M arrest, which was rescued by pifithrin-α. Genetic silencing of POLR1A recapitulated IRBC activation and senescence without causing DNA damage. Time-course analysis showed only marginal γ-H2AX elevation by CX5461 versus robust induction by etoposide. Importantly, etoposide-induced DNA damage failed to enhance RPL5/RPL11-HDM2 binding, suggesting that IRBC activation is not a general consequence of the DNA damage response. Collectively, impaired RiBi drives RIF mainly through the IRBC-p53-senescence axis under our experimental conditions, providing a mechanistic framework for understanding organ toxicities associated with RNA Pol I inhibition.

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