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Updated: Nov 10, 2025
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Published on: March 1, 2024
Rosmarinic acid prevents refractory bacterial pneumonia through regulating Keap1/Nrf2-mediated autophagic pathway and
Wei Zhang1, Cheng Cheng2, Zhou Sha1
1School of Medicine, Nanjing University of Chinese Medicine, 210046, Nanjing, China.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of bacterial pneumonia, featured with exuberant inflammatory cytokine production, extensive oxidative stress and tissue injury. The Keap1/Nrf2 system is the major apparatus essential for host defense against oxidative and electrophilic stresses of both exogenous and endogenous origins, representing a logical target for host-directed strategy to treat severe inflammatory diseases including MRSA-induced pneumonia. In an effort to search therapeutics for bacterial pneumonia, we identify rosmarinic acid (RA) as a covalent modifier of Keap1 and hence an activator of Nrf2. Specifically, RA forms a covalent bond with the cysteine 151 of Keap1 in BTB domain, and blocks its association with Nrf2 for proteasome-mediated degradation. Consequently, RA treatment caused the increased Nrf2 nuclear translocation to initiate antioxidant and mitochondrial biogenic programs, as well as macrophage bactericidal activity through inducing autophagic pathway, which eventually led to expedited bacterial eradication, inflammation resolution, and disease recovery. Collectively, our findings establish RA as a specific inducer of Nrf2 and show its potential to prevent MRSA pneumonia.
Insights
Rosmarinic acid (RA) effectively treats Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia by activating the Keap1/Nrf2 pathway. This natural compound enhances the body's defense against oxidative stress, leading to faster recovery.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a severe condition characterized by high inflammation and oxidative stress.
- The Keap1/Nrf2 system is crucial for cellular defense against oxidative and electrophilic damage, making it a therapeutic target for inflammatory diseases.
- Developing host-directed therapies is essential for combating challenging bacterial infections like MRSA pneumonia.
Purpose of the Study:
- To identify novel therapeutics for bacterial pneumonia by targeting the Keap1/Nrf2 pathway.
- To investigate the potential of rosmarinic acid (RA) as a Keap1 inhibitor and Nrf2 activator.
- To evaluate the efficacy of RA in treating MRSA-induced pneumonia.
Main Methods:
- Identification of rosmarinic acid (RA) as a covalent modifier of Keap1.
- Demonstration of RA's specific binding to cysteine 151 of Keap1, inhibiting Nrf2 degradation.
- Assessment of RA's effects on Nrf2 nuclear translocation, antioxidant and mitochondrial programs, and macrophage bactericidal activity in the context of MRSA infection.
Main Results:
- Rosmarinic acid (RA) covalently binds to Keap1 at cysteine 151, preventing Nrf2 degradation.
- RA treatment promotes Nrf2 nuclear translocation, activating antioxidant and mitochondrial biogenesis pathways.
- RA enhances macrophage bactericidal activity via autophagy induction, leading to improved bacterial clearance and reduced inflammation.
- RA treatment accelerated bacterial eradication, inflammation resolution, and disease recovery in MRSA pneumonia models.
Conclusions:
- Rosmarinic acid (RA) is identified as a specific inducer of the Keap1/Nrf2 pathway.
- RA demonstrates significant therapeutic potential for preventing and treating MRSA-induced pneumonia.
- Targeting the Keap1/Nrf2 system with natural compounds like RA offers a promising host-directed strategy for severe bacterial infections.
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