
June 15th, 2025
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,
- Kuzuoglu-Ozturk et al. discovered that targeting RNA structures with small molecules like zotatifin offers a novel therapeutic strategy for castration-resistant prostate cancer.
- De Siqueira et al. showed that PPARγ activation enhances the translation of adipogenesis-related mRNAs, and highlights the importance of post-transcriptional regulation in adipocyte differentiation.
- Muralidharan et al. provided direct biochemical evidence with the aid of polysome profiling that PERK inhibition relieves translational repression.
Small-molecule RNA therapeutics to target prostate cancer
Cancer Cell, 2025.
Kuzuoglu-Ozturk, D., Nguyen, H.G., Xue, L., Figueredo, E., Subramanyam, V., Liu, I., Bonitto, K., Noronha, A., Dabrowska, A., Cowan, J.E. and Oses-Prieto, J.A.
Eukaryotic initiation factor 4A (eIF4A) is an RNA helicase involved in the initiation of mRNA translation. By inhibiting eIF4A, zotatifin disrupts the translation of specific oncogenic mRNAs, notably the androgen receptor (AR), its splice variant AR-V7, and hypoxia-inducible factor 1α (HIF1α), all of which are critical in castration-resistant prostate cancer (CRPC) progression. In this paper, the author investigated the therapeutic potential of zotatifin, a small-molecule inhibitor of eIF4A, in treating CRPC.
Kuzuoglu-Ozturk et al. employed genome-wide transcriptome, translatome, and proteomic analyses to elucidate zotatifin’s mechanism of action. Polysome profiling technique was used to investigate how the small-molecular inhibitor zotatifin disrupts translation in CRPC. Coupled with luciferase reporter assays, it showed that zotatifin induces structural remodeling of the 5′ untranslated regions (UTRs), and reduces the translation efficiency of key oncogenic transcripts, such as AR, AR-V7 and HIF1α. By analysing mRNA distribution across polysome fractions, the study confirmed that these transcripts were dissociating from actively translating ribosomes, indicating inhibition at the translation level.
Polysome profiling turned out to be a beneficial technique for the identification of the translation inhibition of oncogenic mRNAs, and unveiling target-specific effects of zotatifin. It demonstrated how altering ribosome recruitment can be an effective therapeutic approach in prostate cancer. In vivo studies demonstrated that zotatifin effectively reduces tumor burden and enhances survival in CRPC models, especially when combined with hormone therapy. Additionally, zotatifin-treated tumors exhibited increased sensitivity to anti-androgen therapy and radiotherapy.
These findings suggest that targeting RNA structures with small molecules like zotatifin offers a novel therapeutic strategy for CRPC, termed “translatome therapy,” which could be extended to other malignancies.
Learn more about EIRNA Bio’s polysome profiling service here.
PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity
Cell Reports, 2024
De Siqueira, M.K., Li, G., Zhao, Y., Wang, S., Ahn, I.S., Tamboline, M., Hildreth, A.D., Larios, J., Schcolnik-Cabrera, A., Nouhi, Z. and Zhang, Z.
The paper investigates how obesity affects the adaptability of adipose tissue, focusing on the role of peroxisome proliferator-activated receptor gamma (PPARγ) in remodeling translational machinery within adipose progenitor cells.
Treatment of obese mice with rosiglitazone, a PPARγ agonist, led to significant transcriptional changes in the stromal vascular fraction (SVF) of adipose tissue. Single-cell RNA sequencing revealed an upregulation of ribosomal factors in progenitor and preadipocyte populations, contrasting with the downregulation observed in obesity. The study demonstrated that PPARγ directly regulates the expression of specific ribosomal components, indicating its pivotal role in modulating the translational capacity of adipose progenitor cells.
Polysome profiling indicated that rosiglitazone treatment selectively enhanced the translation of mRNAs involved in adipogenesis and lipid metabolism. This suggests that PPARγ activation facilitates the translational machinery’s capacity to support adipocyte differentiation and function. The application of eukaryotic translation initiation factor 4A (eIF4A) inhibitor was sufficient to block adipogenesis, underscoring the essential role of efficient translation initiation in adipocyte development.
These findings highlight that obesity impairs PPARγ-dependent translational remodeling in adipose progenitors, and that pharmacological activation of PPARγ can partially restore this function, promoting adipose tissue plasticity.
Learn more about EIRNA Bio’s polysome profiling service here.
Inhibition of the eukaryotic initiation factor-2-α kinase PERK decreases risk of autoimmune diabetes in mice
The Journal of Clinical Investigation, 2024
Muralidharan, C., Huang, F., Enriquez, J.R., Wang, J.E., Nelson, J.B., Nargis, T., May, S.C., Chakraborty, A., Figatner, K.T., Navitskaya, S. and Anderson, C.M.
In this study, researchers explored the therapeutic potential of targeting PERK (PKR-like ER kinase) to prevent or delay Type 1 diabetes (T1D).
PERK is a key component of the unfolded protein response (UPR) and the integrated stress response (ISR), pathways activated under conditions of endoplasmic reticulum (ER) stress. In T1D, maladaptive UPR in insulin-producing β cells contributes to their dysfunction and susceptibility to autoimmune attack. Through polysome profiling, it was found that pharmacological inhibition of PERK reversed the mRNA translation block in stressed human pancreatic islets. In non-obese diabetic (NOD) mice, a model for T1D, PERK inhibition delayed diabetes onset, reduced islet inflammation, and preserved β cell mass.
Single-cell RNA sequencing of islets from PERK-inhibited mice revealed reductions in UPR and PERK signaling pathways, along with alterations in antigen-processing and presentation pathways in β cells. Spatial proteomics showed an increase in the immune checkpoint protein PD-L1 in β cells, which may contribute to immune evasion. Additionally, Golgi membrane protein 1 (GOLM1) levels increased following PERK inhibition and interacted with PD-L1, stabilizing its expression.
These findings suggest that PERK activity enhances β cell immunogenicity and therefore its inhibition may offer a strategy for preventing or delaying the development of T1D.
Learn more about EIRNA Bio’s polysome profiling service here.