Reduction of miR-133a-3p contributes to apoptosis and gasdermin E-mediated pyroptosis of keratinocytes in skin exposed to ultraviolet B radiation

Engagement of regulated cell death in keratinocytes plays a crucial role in the pathogenesis and development of skin disorders associated with UV radiation. However, it remains unclear how microRNAs (miRNAs) participate in the regulation of UV-caused keratinocyte death. In this study, we found that miR-133a-3p was decreased in the epidermis of UVB-challenged mice and UVB-irradiated keratinocyte cell line HaCaT cells. The intradermal injection of agomir miR-133a-3p ameliorated skin damage of UVB-challenged mice, especially epidermal necrosis. Meanwhile, the injection inhibited apoptosis indicator PARP cleavage and pyroptosis indicator GSDME cleavage in the epidermis. In UVB-challenged HaCaT cells, transfection of miR-133a-3p mimic or inhibitor alleviated or aggravated UVB-induced apoptosis and GSDME-mediated pyroptosis respectively. miR-133a-3p was also involved in the effects of metformin treatment on alleviating skin damage in UVB-challenged mice and on inhibiting apoptosis and GSDME-mediated pyroptosis in UVB-irradiated HaCaT cells. We confirmed that CYLD is a target gene of miR-133a-3p and participates in the protective effects of miR-133a-3p on inhibiting UVB-caused apoptosis and GSDME-mediated pyroptosis in keratinocytes. This study indicates a pivotal role for miR-133a-3p of keratinocytes in UVB-caused skin damage. Alleviating skin photodamage by restoring the decrease of miR-133a-3p can be considered a potential therapeutic approach.