Document Type

Article

Publication Date

2025

Publication Title

Respiratory Research

Volume

26

Issue

1

Pages

299 (1-13)

DOI

10.1186/s12931-025-03349-9

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global health crisis, marked by high transmissibility and virulence. Despite widespread vaccination efforts, effective treatments for COVID-19, particularly for severe cases leading to Acute Respiratory Distress Syndrome (ARDS), remain limited. This study investigates the efficacy of KVX-053, a protein tyrosine phosphatase type IVA (PTP4A3) small molecule inhibitor, in modulating SARS-CoV-2-induced inflammation and lung injury using in vitro cell models and in vivo K18-hACE2 transgenic mice. KVX-053 reduced in vitro pro-inflammatory cytokine expression, including TNFα, CXCL10, and CXCL11, without impacting viral replication or cell viability. K18-hACE2 mice treated with KVX-053 demonstrated marked improvement in clinical scores and reduced histological evidence of lung injury compared to untreated SARS-CoV-2-infected controls. KVX-053 mitigated the activation of key inflammatory mediators in the lung, including NLRP3 inflammasomes, IL-6, and phosphorylated STAT3, effectively curbing the “cytokine storm” associated with severe COVID-19. Importantly, treatment preserved lung parenchymal integrity, reduced edema, and minimized macrophage infiltration. Our findings highlight PTP4A3 as a potential critical regulator of the inflammatory response during SARS-CoV-2 infection. KVX-053, a potent and selective PTP4A3 inhibitor, emerges as a promising host-directed therapeutic strategy for mitigating ARDS and inflammation-driven lung injury in SARS-CoV-2 and potentially other respiratory viral infections. Future studies are required to optimize dosing strategies, elucidate precise molecular mechanisms, and validate these findings in clinical settings.

Rights

© The Authors 2025.

This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original authors and the source, provide a link to the Creative Commons license, and indicate if you modified the licensed material. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Data Availability

Article states: "Data sets generated during the current study are available from the corresponding author on reasonable request."

Original Publication Citation

Colunga-Biancatelli, R. M. L., Solopov, P. A., Woodson, C. M., Allen, I. C., Akhrymuk, I., Akhrymuk, M., Heath, B. N., Ivester, H. M., Day, T., Austin, D. E., Kehn-Hall, K., Lazo, J. S., Sharlow, E. R., & Catravas, J. D. (2025). The PTP4A3 inhibitor KVX-053 reduces Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virulence, inflammation, and development of acute lung injury in K18-hACE2 mice. Respiratory Research, 26(1), 1-13, Article 299. https://doi.org/10.1186/s12931-025-03349-9

ORCID

0000-0002-1174-3876 (Colunga Biancatelli), 0000-0002-1705-027X (Solopov), 0000-0002-5098-295X (Catravas)

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