Licochalcone D modulates macrophage ferroptosis via suppression of VPS4A-mediated lipophagy to alleviate MRSA pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) represents a predominant multidrug-resistant pathogen that may cause severe bacterial pneumonia. Alveolar macrophages (AMs) serve as the first defensive line against respiratory infections to maintain tissue homeostasis. Licochalcone D (Lico D), a bioactive flavonoid from Glycyrrhiza uralensis, demonstrates protective efficacy against various pulmonary disorders. However, the potential of Lico D to modulate innate immune responses of AMs against bacterial pneumonia and the underlying mechanisms remain unexplored. We herein demonstrate that Lico D remarkably alleviates MRSA-induced pneumonia and protects AMs from ferroptosis. This protective effect is mediated through the suppression of mitochondrial oxidative stress and, more importantly, modulation of lipid metabolism. Specifically, our data elucidate that Lico D directly targets the vacuolar protein sorting 4 homolog A (VPS4A), a newly identified sensor for lipid droplets (LDs), and disrupts its interaction with LC3 for lipophagy to generate free fatty acids (FFAs). Accordingly, Lico D treatment lessens lipid peroxidation (LPO) and hence ferroptosis of macrophages, leading to efficient antibacterial response and inflammation resolution. Collectively, we uncover the VPS4A-targeting and AMs-protecting effects of Lico D, providing new insights into the pathogenesis of MRSA pneumonia and the treatment of critical biotic-resistant pathogens.