<p>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.</p>