Oridonin mitigates bacterial pneumonia by regulating mitochondrial integrity and ferroptosis via targeting KEAP1/NRF2 signaling.

Methicillin-resistant Staphylococcus aureus (MRSA) is a highly virulent and drug-resistant pathogen frequently causing bacterial pneumonia. Currently, there are limited effective treatments available due to the rapidly evolving resistance of bacteria. Therefore, there is an urgent need to develop novel therapies that focus on host-pathogen interactions. Oridonin is a naturally occurring diterpenoid with multiple pharmacological effects, but its therapeutic potential in bacterial pneumonia, as well as its action mode, remains largely unknown. Here, we demonstrated that oridonin conferred protection against MRSA pneumonia. Macrophages, the major innate immune cells against respiratory infection, exhibited enhanced bactericidal capability, alleviated inflammatory response, and resistance to ferroptosis upon oridonin treatment. Importantly, we further showed that oridonin covalently associates with the Kelch-like ECH-associated protein 1 (KEAP1), hindering its binding by nuclear factor erythroid 2-related factor 2 (NRF2). Enhanced activation of NRF2 subsequently activated the genes responsible for mitochondrial lipid peroxidation and iron homeostasis, thereby orchestrating the activity and survival of alveolar macrophages. Collectively, we present the first evidence demonstrating the therapeutic potential of oridonin in combating drug-resistant bacterial pneumonia, establishing it as a novel regulator of both mitochondrial and ferroptotic pathways. This may have significant implications for the development of host-directed therapies against formidable pathogens.