Nd:YAG1064nm laser functions against by inducing PANoptosis via the regulation of ZBP1-induced PANoptosome activation.

BACKGROUND

Due to the emergence of drug resistance in recent years, there is a need for new non-pharmacological treatment methods for sporotrichosis. Our previous study demonstrated that the Nd:YAG1064nm laser exhibited remarkable antifungal activity against , but its exact mechanism remains unclear. This study aimed to detect PANoptosis regulatory protein ZBP1 expression in the skin lesions of patients with sporotrichosis, reveal the exact mechanism of Nd:YAG1064nm laser against sporotrichosis, and provide novel targets and methods for the diagnosis, assessment, and treatment of sporotrichosis.

METHODOLOGY/PRINCIPAL FINDINGS: The ZBP1 level of 60 patients with sporotrichosis (≤3 months;  = 30 and >3 months;  = 30) and 30 HC were retrospectively reviewed using immunohistochemistry. The morphological changes, Hoechst/PI apoptosis and necroptosis preliminary exploration analysis, DNA fragmentation, calcium determination, and metacaspase activation were investigated . For the studies, mice were infected with and then treated with a laser, and their footpad skin lesions and changes in the histology of tissue samples were compared. Changes in the levels of ZBP1, PANoptosome [RIPK1, RIPK3, Fas-associated death domain protein (FADD), CASP8], pyroptosis (CASP1, GSDMD), apoptosis (CASP3), and necroptosis (MLKL) related proteins were assessed using immunohistochemistry, whereas the levels of interleukin 17 (IL-17) and interferon gamma (IFN-γ) in peripheral blood were tested by enzyme-linked immunosorbent assay. ZBP1 expression was significantly increased in -infected patients. Laser treatment effectively inhibited the growth of , destroying its morphological structure, and maybe inducing apoptosis and necroptosis. Moreover, DNA fragmentation, calcium release into the cytoplasm, and metacaspase activation were observed. In addition, laser treatment demonstrated a clear therapeutic effect in animal models of sporotrichosis, which can lead to PANoptosis-related apoptosis, pyroptosis, and necroptosis. Immune response-related macrophages perceive nucleic acid level changes through ZBP1 to recognize and induce PANoptosis by activating the PANoptosome (RIPK1/RIPK3/FADD/CASP8) complex with a Th1/Th17 cell response to combat sporotrichosis.

CONCLUSION

Nd:YAG1064nm laser mediated PANoptosis resistance to sporotrichosis via ZBP1-PANoptosome-PANoptosis pathway.