Ganoderma atrum polysaccharide interferes with TLR4 against PD-1 inhibitors-induced carditis via NF-κB-NLRP3 pathway driven by IRF1/VEGFA/14–3-3γ axis in Lewis lung carcinoma mice

Carditis were fatal immune-related adverse events of PD-1 inhibitors which constituted major advancements in lung cancer. Study aimed to determine effects of Ganoderma atrum polysaccharides (PSG) on PD-1 inhibitors-induced carditis in Lewis lung carcinoma (LLC) mice. Firstly, PSG (12.5, 25 and 50 mg/kg body weight) significantly mitigated carditis without affecting PD-1 inhibitors-mediated anti-tumor value. Briefly, TLR4, NF-κB p65, NLRP3, IL-1β and IFN-γ expressions were significantly elevated in PD-1 inhibitors-treated LLC mice. Besides, oxidative stress was presented by reducing antioxidant enzyme activities and enhancing ROS generation and MDA contents, while PSG administration suppressed these changes. Mechanically, results suggested PSG-1 could directly bind to TLR4. Furthermore, IRF1 was up-regulated during TLR4 signaling-mediated carditis. Meanwhile, IRF1-mediated VEGFA/14–3-3γ axis was involved in carditis. Collectively, our findings proposed IRF1/VEGFA/14–3-3γ axis as a critical mechanism initiating TLR4 signaling cascade referring to NF-κB-NLRP3 pathway, thereby offered a mechanistic insight for understanding cardioprotection of PSG in LLC mice. • PSG ameliorated PD-1 inhibitor-induced myocarditis and oxidative stress. • PSG-induced cardiac protection was linked to the direct binding of TLR4. • PSG inhibits carditis via the TLR4-NF-κB-NLRP3 pathway. • The IRF1/VEGFA/14–3-3γ axis was implicated in the inflammatory regulation of PSG.