5-Methyladenosine (m5C) patterns may serve as a potential biomarker for the identification of patients with idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonia (CHP), according to findings from a study conducted in Shanghai, China, and published in Scientific Reports.

Although it is well recognized that m5C modification controls biological functions and gene expression patterns in the oncologic arena, the effect of m5C modification in patients with IPF or CHP remains to be elucidated. 

The researchers of the current analysis posited that m5C regulators control the mechanism that triggers  the development of IPF and/or CHP. They assessed the functions of m5C regulators in the classification and diagnosis of IPF and CHP according to the GSE150910 data set. Their findings disclosed m5C regulator-mediated RNA methylation modification patterns and immune microenvironment infiltration characterization, thus demonstrating that this genetic factor may play a potential role as an immunotherapeutic agent.

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Tissue was isolated from lung transplants or surgical lung biopsies from 288 samples—103 from patients with IPF, 82 from individuals with CHP, and 103 from unaffected controls. Using differential expression analysis between the patients with IPF/CHP and the corresponding controls, the investigators screened 12 m5C regulators. Of these, the following 5 candidate m5C regulators were screened with the use of random forest and nomogram models, in an effort to predict the risk for IPF:

  • Tet methylcytosine dioxygenase 2
  • NOP2/Sun RNA methyltransferase 5
  • Y-box binding protein 1
  • tRNA aspartic acid methyltransferase 1
  • NOP2/Sun RNA methyltransferase 3

Read more about experimental therapies for IPF

The researchers used the consensus clustering method to divide the samples with different patterns of m5C into m5C cluster A and m5C cluster B. They then calculated immune cell infiltration scores with single-sample gene set enrichment analysis, analyzed immune cell infiltration and function, and identified candidate small-molecule therapeutic agents for patients with IPF/CHP.

Results of the study showed that a statistically significant association with type 2 T helper cells and mast cells was observed in cluster A compared with cluster B ( P <.001 and <.01, respectively). In contrast, cluster B demonstrated a closer association with eosinophils (P <.05).  

In addition, cluster A revealed higher immune activity compared with cluster B. In fact, m5C cluster A received a higher immune score (P =.00016) and stromal score (P =.093) than cluster B. Further, generated violin plots that visualized programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) demonstrated that expression of PD-1/PD-L1was upregulated significantly in cluster A (P <.001).

“In summary, our findings revealed the role of m5C methylation regulators in the development of IPF,” the researchers explained. “These genetic factors have potential to distinguish patients with IPF and CHP, thus are expected to be used in developing new immunotherapy strategies for these patients,” they concluded.


Zhou Y, Hu Z, Sun Q, Dong Y. 5-methyladenosine regulators play a crucial role in development of chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. Sci Rep. Published online April 12, 2023. doi:10.1038/s41598-023-32452-4