Targeting PTP4A3 with KVX-053 mitigates alcohol-amplified SARS-CoV-2 spike protein-induced acute lung injury.

Introduction: Chronic alcohol exposure is associated with increased vulnerability to acute respiratory distress syndrome (ARDS), and emerging evidence suggests that this susceptibility extends to the severe respiratory manifestations of COVID- 19. The SARS-CoV-2 Spike Protein S1 subunit (S1SP) can independently trigger robust inflammatory and vascular injury responses in the lung, and our prior work demonstrated that chronic alcohol consumption markedly intensifies these effects in mice. PTP4A3 phosphatase is a key regulator of inflammation and endothelial barrier function. In this study, we investigated whether the PTP4A3 inhibitor KVX-053 can counteract alcohol-enhanced S1SP-induced lung injury in K18-hACE2 mice. Methods: Animals were maintained on control or chronic ethanol diets, intratracheally exposed to S1SP, and treated with KVX-053 once a day for the next 3 days. Results: Seventy-two hours after S1SP exposure, ethanol-fed mice exhibited significantly greater leukocyte accumulation and protein leakage in bronchoalveolar lavage fluid, alongside heightened production of IL-6, TNF-α, and TGF-β. These amplified responses were accompanied by increased activation of NF-κB, STAT3, and the NLRP3 inflammasome, as well as elevated ACE2 expression. Conclusions: KVX-053 markedly blunted each of these alcohol-dependent injury parameters, reducing cytokine levels, normalizing barrier permeability, and suppressing downstream inflammatory signaling.