Therapeutic Efficacy of the Supersulfide Donor NAC‐S2 in Influenza Virus Pneumonia via Suppression of Excessive Inflammatory Responses

ABSTRACT Influenza pneumonia is characterized by excessive inflammatory responses that contribute to severe lung injury and mortality. Supersulfides, endogenously produced cysteine‐derived persulfides and polysulfides, exert potent antioxidant, anti‐ferroptotic, and anti‐inflammatory activities; however, their therapeutic potential after disease onset remains unclear. Here, we investigated the efficacy of N ‐acetylcysteine tetrasulfide (NAC‐S2), a highly water‐soluble and cell‐permeable supersulfide donor, in a mouse model of influenza A virus (IAV)‐induced pneumonia. Subcutaneous administration of NAC‐S2 rapidly elevated systemic levels of cysteine‐ and glutathione‐derived supersulfides. In therapeutic treatment starting 2 days post‐infection, when body weight loss and clinical signs had already developed, NAC‐S2 significantly improved survival and mitigated body weight loss compared with vehicle and oxidized NAC controls. Metabolomic analysis revealed that influenza virus infection depleted lung glutathione persulfide (GSSH), while NAC‐S2 effectively restored tissue GSSH levels. NAC‐S2 treatment markedly reduced pulmonary interleukin (IL)−1β and IL‐6 production without affecting viral load or Type‐I interferon responses. Furthermore, NAC‐S2 suppressed NLRP3 inflammasome activation and gasdermin D expression, leading to decreased infiltration of CD3 + T cells and myeloperoxidase‐positive neutrophils. Histopathological analyses confirmed that NAC‐S2 ameliorated epithelial injury, interstitial edema, and hemorrhage in infected lungs. Collectively, our findings demonstrate that NAC‐S2 exerts therapeutic benefit even after the onset of severe influenza pneumonia, primarily by replenishing supersulfides and alleviating excessive inflammatory responses. Supersulfide donors represent a promising class of adjunctive therapeutics for severe viral pneumonia.