Lysine-Specific Histone Demethylase 1A Contributes to Cutaneous Psoriatic Lesions by Regulating Ferroptosis

Abstract

Background: Psoriasis is a prevalent immune-mediated chronic inflammatory skin disorder, and the persistent challenge associated with its high recurrence rates remains. This study aimed to investigate the involvement of lysine-specific histone demethylase 1A (KDM1A) in psoriasis pathogenesis. Methods: An imiquimod-induced psoriasis-like dermatitis mouse model was generated and KDM1A knockdown was conducted using lentivirus. Skin appearance was scored and pathological changes were observed. Oxidative stress, lipid peroxidation, inflammatory response, iron accumulation, and ferroptosis-related proteins in the skin were assessed. Afterward, human HaCaT keratinocytes were treated with proinflammatory cytokines to mimic psoriatic conditions and ferroptosis-related proteins were determined. The ferroptosis inducer erastin was used to treat HaCaT keratinocytes, and its influences on oxidative stress and inflammation were assessed. Results: Imiquimod increased the levels of KDM1A, and KDM1A knockdown ameliorated skin psoriatic lesions in mice and reduced inflammatory infiltration. Oxidative stress, lipid peroxidation, iron accumulation, and iron transport-related proteins in skin were also reduced. In HaCaT keratinocytes, KDM1A knockdown similarly mitigated lipid peroxidation and reduced iron transport-related proteins. Importantly, erastin disrupted the inhibition of oxidative stress and inflammation in keratinocytes induced by KDM1A knockdown. Conclusion: This study highlights the significance of KDM1A in psoriasis pathogenesis and suggests that its regulation of ferroptosis may play a critical role in disease development.