SLC7A11 regulates keratinocyte proliferation and inflammatory responses in psoriasis: A metabolic perspective

Summary: Abstract Body: Psoriasis, a chronic inflammatory skin disorder, is characterized by aberrant immune activation and excessive keratinocyte proliferation. Although metabolic dysregulation is increasingly recognized as a hallmark of the disease, the role of amino acid metabolism remains poorly understood. Using constitutive and inducible keratinocyte-specific SLC7A11 knockout mouse models, psoriasis-like inflammation was induced with imiquimod (IMQ). Comprehensive functional analyses were also performed in primary keratinocyte cultures. Notably, SLC7A11 expression was significantly upregulated in psoriatic lesions of both human and mouse origin. Deletion of SLC7A11 in keratinocytes resulted in a marked reduction in proliferation and a substantial attenuation of IMQ-induced inflammatory responses. Furthermore, either genetic ablation or pharmacological inhibition of SLC7A11 reduced neutrophil and macrophage infiltration and diminished the secretion of key inflammatory chemokines, including CXCL2, CXCL5, and CCL20, which are instrumental in sustaining the inflammatory environment in psoriasis. In vitro experiments confirmed the critical role of SLC7A11 in keratinocyte biology. Silencing SLC7A11 impaired DNA synthesis, arrested cell cycle progression, and disrupted essential intracellular signaling pathways necessary for keratinocyte viability and function. Importantly, the proliferation defects caused by SLC7A11 deficiency were completely rescued by supplementation with N-acetylcysteine, highlighting the pivotal role of cysteine metabolism in keratinocyte homeostasis. These findings identify SLC7A11 as a key metabolic regulator in psoriasis, orchestrating keratinocyte proliferation and the inflammatory response. This study not only advances the understanding of the metabolic mechanisms underlying psoriasis but also positions SLC7A11 as a potential therapeutic target for innovative immunosuppressive treatments aimed at alleviating the chronic inflammation associated with this disease. Yuanyuan Wang^{1, 2}, Yuling Shi^{1, 2} 1. Shanghai Skin Diseases Hospital, Shanghai, Shanghai, China. 2. Tongji University School of Medicine, Shanghai, Shanghai, China. Epidermal Structure and Barrier Function