Targeting cathepsin B alleviates activation of IL-17A-netrophils axis to suppress atopic dermatitis

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease lacking therapeutic drugs that address its complex, heterogeneous pathogenesis. By clinical data analysis and AD model verification, our study demonstrated that lysosomal destabilization and the subsequent cytoplasmic release of cathepsins was a critical pathway that amplifies the Interleukin-17A (IL-17A) inflammatory response and promotes AD progression. We revealed that Isoliensinine (IsoL) is a novel therapeutic agent that can target cathepsin B (CTSB) to delay the progression of AD, rather than alleviate symptoms of inflammation. Mechanistically, IsoL significantly suppressed AD and inhibited inflammation, specifically downregulating IL-17A signaling by suppressing dendritic cell mediated Type 17 T-helper cell (Th17) differentiation, thus suppressing neutrophil infiltration. Rescue experiments confirmed that IsoL's anti-inflammatory and AD-suppressing effects were dependent on its inhibition of CTSB-IL-17A-neutrophil axis. These findings highlighted CTSB as a crucial drug target in AD and present IsoL as a promising novel candidate for AD treatment. Overall design: The submission includes ear tissue samples from mice assigned to different experimental groups.Experimental conditions include blank, MC903-induced atopic dermatitis, and Isoliensinine treatment.Biological replicates are included for all groups.