ArticleMolecular medicine (Cambridge, Mass.)2025
Activation of the MEK1-CHK2 axis in macrophages by Staphylococcus aureus promotes mitophagy, resulting in a reduction in bactericidal efficacy.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Mitophagy in pathogenesis and therapeutic implications for infection.Experimental & molecular medicine · 2026Review
- Osteomyelitis: Epidemiology, Classification, Pathophysiology, Clinical Features, Diagnosis, and Management.MedComm · 2026Review
- Analysis of Phosphorylated MEK1 Expression Pattern in Cutaneous Dilated Vessels of Capillary Malformations.The Journal of dermatology · 2026Article
- Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis.Nature communications · 2026Article
- A novel host-based strategy for detecting low-grade prosthetic joint infection using immune cell pattern in synovial fluid.Molecular medicine (Cambridge, Mass.) · 2026Article
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8 authors.
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Abstract
backgroundMacrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in Staphylococcus aureus (S. aureus)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.
methodsIn this study, we established an S. aureus implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic-killing ability, and CHEK2 mitochondrial translocation in S. aureus-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.
resultsPharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during S. aureus infection.
conclusionsWe identified a self-amplifying pathogenic loop in which S. aureus exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic-immune checkpoint and highlight its druggable vulnerability in osteomyelitis.
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