ObjectiveTo investigate the effects of growth differentiation factor 11 (GDF11) on the modulation of macrophage polarization through the mTOR pathway in the context of immune regulation during influenza virus infection.MethodsCells were divided into five groups: negative control (NC), Model, GDF11^+/+, GDF11^－/－, and GDF11^－/－+MHY1485 group. Flow cytometry was employed to assess the expression levels of iNOS and CD86 in RAW264.7 cells across the groups. ELISA kits were utilized to measure levels of inflammatory cytokines and immunoglobulins in the culture supernatants of RAW264.7 cells. The expression levels of GDF11, mTOR pathway proteins, inflammatory cytokines, and immunoglobulins were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, and immunofluorescence assays.ResultsCompared with the NC group, influenza virus RP8 infection promoted M1 polarization of RAW264.7 cells (P<0.05), downregulated GDF11 levels (P<0.05), upregulated inflammatory cytokines (TNF-α, IL-6, and IL-1β) levels (P<0.05), and downregulated immunoglobulins (IgA, IgG, and IgM) levels (P<0.05), while enhancing phosphorylation of mTOR, AMPK, and AKT proteins (P<0.05). In comparison with the Model group, overexpression of GDF11 significantly inhibited M1 polarization of RAW264.7 cells (P<0.05), decreased levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) (P<0.05), increased levels of immunoglobulins (IgA, IgG, and IgM) (P<0.05), and suppressed phosphorylation of mTOR, AMPK, and AKT proteins (P<0.05). Knockout of GDF11 protein significantly promoted M1 polarization in RAW264.7 cells (P<0.05), upregulated the levels of inflammatory factors, downregulated the levels of immunoglobulins (P<0.05), and enhanced the phosphorylation of mTOR, AMPK, and AKT proteins (P<0.05). The mTOR inhibitor MHY1485 effectively suppressed M1 polarization in RAW264.7 cells (P<0.05), reduced levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) (P<0.05), increased levels of immunoglobulins (IgA, IgG, and IgM) (P<0.05), and inhibited phosphorylation of mTOR, AMPK, and AKT proteins (P<0.05).ConclusionGDF11 can mitigate M1 polarization of RAW264.7 cells induced by influenza virus infection through the inhibition of the mTOR signaling pathway, thereby contributing to immune regulatory responses during influenza virus infection.