Fluvoxamine Exerts Anti-influenza A Virus Effects through Inhibiting Apoptosis Pathway

Influenza is a serious respiratory disease with high pathogenicity and mortality rates. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been shown to alleviate inflammation in sepsis animal models and prevent severe complications caused by coronavirus disease 2019 (COVID-19). However, there are currently no reports on the potential anti-influenza effects of fluvoxamine. To investigate whether fluvoxamine has anti-influenza effects and elucidate the mechanisms of its action. This study evaluated the anti-influenza effects of fluvoxamine using H1N1-infected BALB/c mice and found that, compared to the H1N1 infection group, the survival rate of mice in the fluvoxamine intervention group increased by 30% (50 vs. 20%), with a decreased trend in body weight loss and improved lung tissue lesions. In vitro, fluvoxamine significantly increased the cell survival rate at nontoxic doses [(60.77 + 4.42) vs. (79.74 ± 5.43)%, p = 0.0028] and reduced cell damage caused by H1N1 infection. Furthermore, H1N1 infection in lung epithelial cells induces apoptosis, which can be prevented and reduced by fluvoxamine intervention. Fluvoxamine can significantly reduce Annexin V⁺/PI⁺ cell ratio [(28.58 + 3.60) vs. (21.28 ± 4.01)%, p = 0.0273]. In vivo, the anti-apoptotic effect of fluvoxamine was confirmed, and it was shown that fluvoxamine can reduce the number of TUNEL⁺ (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive) cells induced by H1N1 infection. Western blot analysis showed that fluvoxamine can significantly reduce the expression of cleaved caspase-3 and cleaved poly(ADP-ribose)polymerase. This study reveals that fluvoxamine has protective effects against influenza in vitro and in vivo for the first time, and reducing epithelial cell apoptosis may be one of the key mechanisms by which fluvoxamine exerts its anti-influenza effects.