circEPSTI1 regulates miR-942-5p–SERPINE1–AKT1 signaling axis to enhance dengue infection and is suppressed by Tiplaxtinin
7 affiliations
- 1Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Bhopal 462066, India
- 2Department of Microbiology, College of Medicine and Jawaharlal Nehru Memorial Hospital, Kalyani 741235, India
- 3Department of Forensic Medicine and Toxicology, College of Medicine and Jawaharlal Nehru Memorial Hospital, Kalyani 741235, India
- 4Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
- 5Department of Transfusion Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
- 6Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal 462024, India
- 7World Premier International Research Center - Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
Abstract
Circular RNAs (circRNAs) have recently been identified as crucial regulators of gene expression in various diseases. Their role in dengue remains unexplored. In this study, circEPSTI1 induction was observed in peripheral blood mononuclear cells and plasma of dengue patients. The induction of circEPSTI1 is interferon-dependent and enhances DENV infection by sponging the expression of miR-942-5p. The antiviral role of miR-942-5p is mediated by bidirectional inhibition through targeting conserved genomic sequences of the DENV genome of different subtypes across NS1, NS3, and NS5 and the host AKT1 signaling pathway. RNA-seq analysis of DENV-infected circEPSTI1 knockdown A549 cells identified SERPINE1 and AKT1 signaling pathways to be dysregulated significantly. circEPSTI1 relieves the inhibition of miR-942-5p over DENV genomic RNA and the host SERPINE1 to activate AKT1 signaling. The activation of AKT1 signaling facilitates cell survival and enhances DENV replication. The expression of SERPINE1 and circEPSTI1 was upregulated in Dengue patients, and pharmaceutical inhibition of SERPINE1 through Tiplaxtinin inhibits the DENV replication by reducing the expression of circEPSTI1. Overall, our result demonstrates the therapeutic potential of Tiplaxtinin by targeting the circEPSTI1–miR-942-5p–SERPINE1–AKT1 axis in dengue treatment.
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BibTeX
@article{das2026circepsti1,
title = {{circEPSTI1 regulates miR-942-5p–SERPINE1–AKT1 signaling axis to enhance dengue infection and is suppressed by Tiplaxtinin}},
author = {Nilanjana Das and Pandikannan Krishnamoorthy and Kushal Ramrao Junghare and Athira S. Raj and Priyanka Saha and Kuhu Pal and Shouvanik Adhya and Atul Garg and Dheeraj Khetan and Ashok Kumar and Himanshu Kumar},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2602747123},
url = {https://doi.org/10.1073/pnas.2602747123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - circEPSTI1 regulates miR-942-5p–SERPINE1–AKT1 signaling axis to enhance dengue infection and is suppressed by Tiplaxtinin
AU - Nilanjana Das
AU - Pandikannan Krishnamoorthy
AU - Kushal Ramrao Junghare
AU - Athira S. Raj
AU - Priyanka Saha
AU - Kuhu Pal
AU - Shouvanik Adhya
AU - Atul Garg
AU - Dheeraj Khetan
AU - Ashok Kumar
AU - Himanshu Kumar
PY - 2026
DA - 2026/10/26
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2602747123
UR - https://doi.org/10.1073/pnas.2602747123
AB - Circular RNAs (circRNAs) have recently been identified as crucial regulators of gene expression in various diseases. Their role in dengue remains unexplored. In this study, circEPSTI1 induction was observed in peripheral blood mononuclear cells and plasma of dengue patients. The induction of circEPSTI1 is interferon-dependent and enhances DENV infection by sponging the expression of miR-942-5p. The antiviral role of miR-942-5p is mediated by bidirectional inhibition through targeting conserved genomic sequences of the DENV genome of different subtypes across NS1, NS3, and NS5 and the host AKT1 signaling pathway. RNA-seq analysis of DENV-infected circEPSTI1 knockdown A549 cells identified SERPINE1 and AKT1 signaling pathways to be dysregulated significantly. circEPSTI1 relieves the inhibition of miR-942-5p over DENV genomic RNA and the host SERPINE1 to activate AKT1 signaling. The activation of AKT1 signaling facilitates cell survival and enhances DENV replication. The expression of SERPINE1 and circEPSTI1 was upregulated in Dengue patients, and pharmaceutical inhibition of SERPINE1 through Tiplaxtinin inhibits the DENV replication by reducing the expression of circEPSTI1. Overall, our result demonstrates the therapeutic potential of Tiplaxtinin by targeting the circEPSTI1–miR-942-5p–SERPINE1–AKT1 axis in dengue treatment.
SN - 0027-8424
SN - 1091-6490
ER -