Triptolide clears Staphylococcus aureus infection by targeting XIAP to induce host apoptosis while preserving gut microbiota homeostasis [iBMDMs]

Staphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the efficacy of conventional antibiotics. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With the multi-targeting and immunomodulatory properties, Traditional Chinese Medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored. Here, we identified triptolide as a compound that facilitates intracellular clearance of SA and MRSA. Mechanistic studies revealed that triptolide directly binds to the X‑linked inhibitor of apoptosis protein (XIAP) to inhibit XIAP-caspase interaction, thereby releasing caspase inhibition and inducing apoptosis. Moreover, treatment with triptolide reduced bacterial loads and alleviated lung inflammation in mice infected with SA and MRSA, concurrently maintaining microbiota homeostasis and improving metabolic function. Taken together, these findings establish triptolide as a promising lead compound for the development of HDT against SA and MRSA infections.