ZBP1-mediated PANoptosis is a crucial lethal form in diverse keratinocyte death modalities in UVB-induced skin injury.

UVB irradiation induces diverse modalities of regulatory cell death in keratinocytes. Recently, the pattern of coexistence of pyroptosis, apoptosis, and necroptosis has been termed PANoptosis; however, whether PANoptosis occurs in keratinocytes in UVB-induced skin injury remains unclear. We observed that the key molecules of GSDMD-mediated pyroptosis, apoptosis, and necroptosis, which are N-terminal GSDMD, cleaved caspase-3/PARP, and phosphorylated MLKL, respectively, were elevated in keratinocytes of UVB-challenged mice and human skin tissue. Through keratinocyte-specific gene knockout or using corresponding inhibitors, we found that individual inhibition of GSDMD-mediated pyroptosis, caspase-3-mediated apoptosis, or MLKL-mediated necroptosis did not reduce the overall level of keratinocyte death after UVB exposure, and that the other two pathways maintained the activation. However, when the PANoptosome sensor ZBP1 was knocked out, keratinocyte death was reduced and epidermal thickening was alleviated in UVB-challenged mice. In conclusion, our study demonstrated that UVB irradiation induces ZBP1-mediated PANoptosis in keratinocytes, which is a crucial lethal form in diverse keratinocyte death modalities in UVB-induced skin injury. The above findings provide a new insight on the complexity of regulated cell death modalities in keratinocytes exposed to UV irradiation.