Salvianolic Acid B Inhibits <scp>ZBP1</scp>‐Mediated <scp>PANoptosis</scp> in <scp><i>Mycobacterium tuberculosis</i></scp>‐Infected Macrophages by Targeting <scp>TNFR1</scp>

The increasing rates of drug resistance in Mycobacterium tuberculosis (Mtb) have made controlling tuberculosis more challenging. Excessive programmed cell death helps mediate Mtb transmission. Salvianolic acid B (Sal B), a water-soluble extract of Salvia miltiorrhiza, has been reported to inhibit programmed cell death and excessive inflammation. This study aimed to investigate the potential inhibitory mechanism of Sal B on PANoptosis. The inhibitory effect of Sal B on PANoptosis was evaluated by western blotting, ELISA, and other techniques in an in vitro model of Mtb H37Ra-infected macrophages. The roles of ZBP1 and TNFR1 in PANoptosis were explored by small interfering RNA transfection. In addition, the inhibitory effect of Sal B on PANoptosis and the hyperinflammatory response was verified by western blotting, hematoxylin and eosin staining, and immunohistochemistry in an in vivo model of inflammatory injury in the lungs of LPS-infected mice. Sal B inhibited the protein levels of key molecules of Mtb-mediated PANoptosis and hindered the assembly of the PANoptosome consisting of ASC, ZBP1, RIPK1, RIPK3, and Caspase 8. Sal B may further inhibit PANoptosis by binding to TNFR1 and suppressing ZBP1 levels. In addition, the results of in vivo studies verified that Sal B could ameliorate LPS-induced pathological injury in mouse lung tissues. Sal B can target TNFR1 to achieve a regulatory effect on macrophage PANoptosis. This provides new ideas for Sal B as a host-directed therapy drug to attenuate the excessive inflammatory response induced by Mtb infection.