p300-Mediated H3K18 Lactylation Drives Radiation-Induced Pulmonary Fibrosis via VIRMA-Dependent m6A Modification of GATA3.

Authors

Junxuan Yi, Mingwei Wang, Duo Yu, Mingqi Zhao, Xinyan Wang, Shiqi Li, Xiaowen Han, Wei Wei, Shunzi Jin

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77328. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

Radiation-induced pulmonary fibrosis, a devastating thoracic radiotherapy sequela, features aberrant ECM deposition and irreversible loss of functional lung architecture. However, the exact molecular mechanisms governing AECII dysfunction and fate transition during RIPF remain poorly understood. Here, we identify a novel metabolic-epigenetic-epitranscriptomic cascade that orchestrates the pro-fibrotic fate of AECIIs. We demonstrate that radiation exposure triggers a glycolytic shift in AECIIs, resulting in pathological intracellular lactate accumulation. This metabolic stress is directly coupled to chromatin remodeling via p300-mediated H3K18la at the VIRMA promoter, driving its robust transcriptional activation. Consequently, elevated VIRMA promotes a pro-fibrotic epitranscriptomic landscape by increasing m6A enrichment on the GATA3 mRNA. Recognition of this modification by the m6A reader YTHDF1 extends GATA3 mRNA half-life. The ensuing GATA3 accumulation initiates EMT and exacerbates ECM deposition. Strikingly, utilizing AECII-specific Virma conditional knockout mice, we confirmed the essential role of this axis in vivo; genetic ablation of Virma preserved alveolar integrity and conferred resistance to radiation-induced fibrogenesis. Furthermore, pharmacological inhibition of the H3K18la writer p300 using C646 abrogated the fibrotic phenotype. Collectively, our findings elucidate how radiation-induced metabolic reprogramming is durably inscribed into the epigenome to dictate cell fate, offering a therapeutic rationale for targeting the H3K18la/VIRMA/GATA3 axis in RIPF.

PMID:
42635958
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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