Recent Publications Harnessing the Power of Translatomics

Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.

In this week’s Sunday papers,

  • Li et al. show that m5C-dependent YBX1 binding increases RNF115 ribosome loading, and YBX1-mediated mRNA circularisation promotes translation reinitiation.
  • Gong et al. reveal that negative-strand rORFs in CGMMV are actively translated, uncovering hidden viral proteomes and virulence factors.
  • Xu et al. underline that Azithromycin slows Pseudomonas aeruginosa resistance to ceftazidime avibactam by translationally repressing rpoS, reducing mutation and resistance evolution.

Targeting YBX1‐m5C mediates RNF115 mRNA circularisation and translation to enhance vulnerability of ferroptosis in hepatocellular carcinoma

Clinical and Translational Medicine, 2025.

Li, O., An, K., Wang, H., Li, X., Wang, Y., Huang, L., Du, Y., Qin, N., Dong, J., Wei, J., Sun, R., Shi, Y., Guo, Y., Sun, X., Yang, Y., Yang, Y.-G., Kan, Q., and Tian, X.

Sunday Paper 1

The study reveals that the RNA-binding protein YBX1 drives hepatocellular carcinoma (HCC) progression by inhibiting ferroptosis, a form of cell death linked to lipid peroxidation. Ribo-seq demonstrated that RNF115 is not merely transcriptionally regulated but actively enhanced at the level of translation when YBX1 binds m5C-modified RNF115 mRNA.

YBX1 binds to 5-methylcytosine (m5C) sites on the RNF115 mRNA 3′-UTR, recruits the translation factor EIF4A1, and promotes mRNA circularisation and efficient translation in an m5C-dependent manner. RNF115, an E3 ubiquitin ligase, in turn ubiquitinates dihydroorotate dehydrogenase (DHODH) at Lys27, preventing its autophagic degradation and suppressing ferroptosis. The m5C methyltransferase NSUN2 catalyses RNF115 m5C  mRNA methylation, facilitating this regulatory axis. High YBX1/RNF115 expression correlates with poor patient survival, highlighting this pathway as a potential prognostic marker and therapeutic target to enhance ferroptosis vulnerability in HCC.

Learn more about EIRNABio’s ribosome profiling services here.

Cucumber green mottle mosaic virus encodes additional small proteins with specific subcellular localizations and virulence function

Science China Life Sciences, 2025.

Gong, P., Gao, M., Chen, Y., Zhang, M., Huang, Y., Hu, X., Zhao, S., Zhang, H., Pan, M., Cao, B., Shen, Q., Liu, Y., Lozano-Durán, R., Wang, A., Zhou, X. and Li, F.

Sunday Paper 2

This study reveals that Cucumber green mottle mosaic virus (CGMMV), a positive-sense single-stranded RNA virus, encodes previously unrecognized small proteins from reverse open reading frames (rORFs) on the negative strand. Using mass spectrometry and ribosome profiling, the authors confirmed that these rORFs produce small proteins, likely translated via internal ribosome entry sites (IRES). Functional analyses showed that mutating two rORFs significantly reduced CGMMV virulence, while ectopic expression restored pathogenicity, demonstrating their importance for infection. The rORF-encoded proteins exhibit distinct subcellular localizations: one localizes to peroxisomes and interacts with the viral 126-kDa replication protein, while another localizes to the cell membrane and nucleolus. They also identified the peroxisomal protein PEX3 as mediating targeting of the peroxisome-localized rORF protein. This work expands the known tobamoviral proteome and highlights novel virulence factors and subcellular targets in viral infection.

Learn more about EIRNABio’s ribosome profiling services here.

Azithromycin represses evolution of ceftazidime/avibactam resistance by translational repression of rpoS in Pseudomonas aeruginosa

Journal of Bacteriology, 2025.

Xu, C., Feng, J., Zhou, Y., Ren, H., Pan, X., Chen, S., Liu, X., Li, G., Li, J., Geng, B., Gao, L., Cheng, Z., Jin, Y., Ha, U., Jin, S., Lamont, I.L., Pletzer, D., and Wu, W.

Sunday Paper 3

The study identifies a mechanism by which azithromycin slows the evolution of resistance to the β‑lactam/β‑lactamase inhibitor combination ceftazidime‑avibactam (CZA) in Pseudomonas aeruginosa. Combining CZA with subinhibitory concentrations of azithromycin significantly repressed resistance development in vitro and in a neutropenic mouse model, compared with CZA alone. Transcriptome analysis showed that azithromycin reduced expression of genes involved in stress‑induced mutagenesis, notably the alternative sigma factor rpoS, which promotes mutation and resistance.

Ribosome profiling revealed that azithromycin induces global ribosome redistribution and enhanced stalling at the 5′ terminus of the rpoS mRNA, particularly at rare and less frequently used codons, leading to translational repression of rpoS. This repression decreases rpoS mRNA levels and reduces mutation frequency, slowing resistance evolution. Mutating these rare codons to more common ones lessened azithromycin’s repression of rpoS translation and increased resistance mutation frequencies, confirming the mechanism. The findings suggest that azithromycin‑CZA combination therapy could be a promising strategy to delay resistance emergence in P. aeruginosa infections.

Learn more about EIRNABio’s ribosome profiling services here.