LAUSR

Mycobacterium abscessus (MAB) is an increasingly recognized rapidly growing nontuberculous mycobacterial pathogen whose infection is particularly challenging to treat due to its antibiotic resistance and persistence, necessitating the exploration of innovative treatment strategies. In this study, it is demonstrated that punicalagin, a polyphenolic compound derived from pomegranate, enhances macrophage antibacterial activity by promoting autophagy rather than exerting direct bactericidal effects. In THP‐1 macrophages, punicalagin at 40 µm reduced intracellular MAB by 47% at 24 h post‐infection. Mechanistically, punicalagin treatment induced an increase LC3‐II/LC3‐I ratio and p62 degradation. It is found that punicalagin promotes autophagy by enhancing mitochondrial stability through upregulating SIRT1 and activating the SIRT1/FoxO3 axis, which in turn inhibits the PI3K/Akt/mTOR pathway. In vivo mouse studies show that punicalagin treatment significantly reduce the MAB burden in the lungs and alleviates the inflammatory cell infiltration in infected lung tissue. The investigation reveals a striking cellular selectivity in its mechanism of action. Punicalagin demonstrates preferential efficacy in interstitial macrophages, while exhibiting little impact on the MAB burden within alveolar macrophages. Transcriptomic analysis of sorted macrophage populations confirms a significant enrichment of autophagy and lysosome‐related pathways specifically in IMs from punicalagin‐treated mice. Taken together, the findings uncover a novel host‐directed therapeutic strategy against MAB infection.