L-Citrulline Attenuates Keratinocyte Activation and Modulates ASS1 Expression in Psoriasis-Like Mice

Psoriasis is a common chronic inflammatory skin disease with a high prevalence, which seriously impairs patients' quality of life. Although the clinical application of biologics has achieved satisfactory therapeutic effects, it still has certain limitations, such as high recurrence rate and poor clinical response in some patients. Therefore, it is urgent to further explore the pathogenesis of psoriasis to identify novel research directions and therapeutic targets for the prevention and treatment of this disease.

An imiquimod (IMQ)-induced psoriasis-like mouse model was established in this study. Multi-omics profiling and molecular biological experiments were performed to explore the regulatory mechanism underlying psoriasis progression. Keratinocyte functional assays and pharmacological intervention were conducted to verify the biological function of L-citrulline and ASS1.

L-citrulline levels were significantly decreased in the lesional skin of psoriatic mice. L-citrulline treatment substantially alleviated psoriasis-like pathological phenotypes and restrained keratinocyte hyperactivation, including excessive proliferation, migration, and inflammatory responses. Mechanistically, L-citrulline markedly downregulated the expression of ASS1, which was highly upregulated in psoriatic skin lesions. Functional validation demonstrated that ASS1 overexpression promoted keratinocyte activation, whereas pharmacological inhibition of ASS1 efficiently suppressed keratinocyte hyperactivation in vitro and ameliorated IMQ-induced psoriasis-like skin lesions in vivo.

ASS1 serves as a critical regulator and promising therapeutic target for psoriasis. L-citrulline supplementation or ASS1 inhibition effectively blocks keratinocyte hyperactivation and retards psoriasis progression, providing a novel and feasible therapeutic strategy for psoriasis treatment.