Targeting Cathepsin B-mediated pyroptosis in fibroblasts alleviate ultraviolet-induced skin inflammation and injury

Exposure to ultraviolet (UV) radiation is known to cause acute skin damage and inflammation, yet the underlying molecular mechanisms and cellular damage involved in this process remain poorly understood. In this study, we provide compelling evidence that UV-induced fibroblast pyroptosis not only triggers a cascade of macrophage inflammatory responses but also could represents a important mechanism in the pathogenesis of acute sunburn. We further investigate the intricate interplay between pyroptotic fibroblasts (Pyr-Fbs) and macrophages, elucidating the resultant alterations in macrophage phenotypes and the subsequent inflammatory cascade. At the molecular level, our study reveals a significant upregulation of cathepsin B (CTSB) expression in fibroblasts upon UV exposure. Furthermore, we demonstrated that utilization of skin microneedles (MNs) loaded antisense oligonucleotides (ASO) targeting Ctsb enables controlled release, effectively mitigating the detrimental effects of UV-induced damage and inflammation. Importantly, our findings highlight the critical role of CTSB in regulating the activity of the NLRP3 inflammasome through its binding to the leucine-rich repeat (LRR) domain, thereby modulating the progression of pyroptosis and subsequent macrophage-driven inflammation. Overall, our findings shed new light on the significance of CTSB in UV-induced Pyr-Fbs and propose a promising clinical treatment strategy involving ASO therapy delivered via MNs.