Salvianolic acid B exerts a protective effect against ZBP1-mediated PANoptosis in macrophages infected by Mycobacterium tuberculosis through its inhibition of the TNF- α/TNFR1 signaling pathway

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Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis (Mtb). The increasing rates of drug resistance in Mtb have made controlling TB more challenging, creating an urgent need for new treatment strategies. The interplay between macrophages and Mtb governs host susceptibility and immune evasion by manipulating programmed cell death (PCD) pathways and inflammatory responses. During Mtb infection, excessive programmed cell death can harm the host, as it aids in clearing the pathogen and promotes Mtb growth. If the infection is not cleared in a timely manner, excessive inflammation can further damage the host's tissues. A recent discovery called PANoptosis refers to a type of regulated inflammatory cell death that involves pyroptosis, necroptosis, and apoptosis, and it may occur after Mtb infection. Here, we report that Salvianolic acid B (Sal B), a water-soluble extract of Salvia miltiorrhiza, may act as a potential host-directed therapy (HDT) agent to inhibit Mtb-induced PANoptosis and suppress the intense inflammatory response. Mechanistically, Sal B could inhibit the TNF-α/TNFR1 signaling pathway, thereby inhibiting the innate immune sensor ZBP1 and achieving a regulatory effect on macrophage PANoptosis. We also observed that Sal B inhibited a large multi-protein signaling complex formed by ZBP1, ASC, caspase-8, RIPK1 and RIPK3, ultimately inhibiting inflammatory cell death. Overall, this study provides a deeper understanding of the roles these biomolecules play in innate immunity and inflammatory cell death during Mtb infection. The findings highlight Sal B as a potential HDT agent capable of inhibiting PANoptosis in macrophages and mitigating the excessive inflammatory response induced by Mtb infection. Notably, further research is needed to explore the therapeutic potential of Sal B in combatting Mtb and its implications as a potential future treatment option.