Psoriasis is a chronic and common immune-mediated skin disease [1,2] that occurs worldwide and can affect the skin, joints, or both [3]. It is characterized by raised erythematous plaques accompanied by silvery or white multi-layered scales [4,5]. This condition exerts a significant negative impact on both the physical and mental health of patients [2], and currently, there is no complete cure. Psoriasis mainly results from the dysregulation of cytokines or chemokines secreted by immune cells, which leads to a persistent inflammatory state in the skin's microenvironment [6], thereby causing tissue damage and disease progression. Although current treatment methods offer a variety of options, including topical therapies, phototherapy, systemic immunomodulators, and biologics, all aiming to relieve symptoms and improve the quality of life [7,8], challenges remain. Adverse reactions, treatment resistance, high costs, and differences in responses among individuals all affect the treatment outcome [9]. Therefore, a better understanding of the pathogenesis is of great significance for the development of treatment methods for psoriasis.

Forkhead box C1 (FOXC1) belongs to the FOX transcription factor family. Members of the FOX family are a group of transcription factors with a winged-helix or forkhead-shaped DNA-binding domain composed of approximately 100 amino acids [10,11]. This family plays crucial roles in development, metabolism, cancer, and aging [12]. Currently, several studies have demonstrated that FOXC1 is involved in normal embryonic development and regulates the development and functions of various organs [11,13]. Research has shown that FOXC1 exerts an inhibitory effect on oxidative stress [14] and inflammation [15]. In brain injury, the knockdown of FOXC1 promotes the expression of pro-inflammatory factors TNF-α and IL-1β [16]. Moreover, it has been reported that in the sweat glands of mice with FOXC1 knockout, the expression of pro-inflammatory factors S100A8 and S100A9 is significantly upregulated [17]. The expression and secretion of these two factors are also regarded as markers of psoriasis [[18], [19], [20]]. In psoriatic skin lesions, the secretion of S100A8 and S100A9 is significantly upregulated [21,22]. After knocking out S100A9 in a mouse skin inflammation model, psoriasis-like skin diseases and inflammation are significantly alleviated [23]. However, the function of FOXC1 in psoriasis is still unknown.

Accordingly, in this work, we mainly focused on exploring the function and underlying mechanism of FOXC1 in psoriasis. IMQ-induced psoriasis mice and M5-induced HaCat cells were used as in vitro and in vivo models. Our results showed that FOXC1 is downregulated in IMQ-induced psoriatic mice and M5-induced HaCat cells. The overexpression of FOXC1 alleviated psoriasis-like skin inflammation and oxidative stress. Mechanistic studies suggested that FOXC1 may play a protective role in psoriasis through the transcriptional regulation of suppressor of cytokine signaling 3 (SOCS3).