Abstract Rationale The frequent co-occurrence of idiopathic pulmonary fibrosis (IPF) and lung cancer (LC), along with their shared risk factors and molecular pathological features, strongly suggests a shared pathogenic origin within the alveolar epithelium. We hypothesize that epigenetic inactivation of the tumor suppressor RUNX3 serves as a unifying initiating event that synchronously drives the pathogenesis of both diseases by orchestrating the activation of core pathological programs—epithelial-mesenchymal transition (EMT) and glycolytic reprogramming. Methods RUNX3 and DNMT3A expression was assessed in human IPF and LC tissues and matched controls via immunohistochemistry (IHC) and immunofluorescence. In vitro, RUNX3 was knocked down by siRNA in a549 cells. TGF-β1 was used to induce cellular changes. RUNX3 promoter methylation was detected by Methylation-Specific PCR (MSP), and DNMT expression was measured by qPCR. RNA-seq was performed on RUNX3-knockdown cells. Key proteins in EMT and glycolysis were analyzed by Western Blot. Lactate production was measured biochemically. Results RUNX3 protein was significantly downregulated in both human IPF and LC tissues compared to controls, while its methyltransferase, DNMT3A, was upregulated. In vitro, TGF-β1 treatment induced RUNX3 promoter methylation, increased DNMT3A expression, and promoted RUNX3 translocation from the nucleus to the cytoplasm. RNA-seq of RUNX3-knockdown cells revealed significant upregulation of the glucose transporter GLUT3 (SLC2A3) and enrichment of glycolytic pathways. Functional validation confirmed that RUNX3 knockdown promoted GLUT3 translocation to the plasma membrane, a process preceded by the enhancement of lactate production and increased expression of key glycolytic enzymes (HK2, PKM2, LDHA). Furthermore, RUNX3 knockdown induced EMT, evidenced by decreased E-cadherin and increased N-cadherin and Vimentin. Conclusion DNMT3A-mediated RUNX3 promoter methylation acts as a unifying initiating event that co-drives the pathogenesis of pulmonary fibrosis and lung cancer by synchronously activating EMT and glycolytic reprogramming in alveolar epithelial cells. Targeting this common epigenetic axis may offer a novel strategy for the combined prevention and treatment of both diseases. Additionally, RUNX3 methylation holds promise as an early detection biomarker for pulmonary fibrosis, addressing a critical unmet need. This abstract is funded by: National Natural Science Foundation of China (NSFC)
Yang et al. (2026) studied this question.