ACSL4 is overexpressed in psoriasis and enhances inflammatory responses by activating ferroptosis

More and more studies have shown that ferroptosis is closely related to the progression of various diseases, but the significance of ferroptosis in psoriasis is still rarely explored. The detection of plasma and psoriatic lesions found that the contents of MDA and ROS were significantly increased, while the contents of SOD and GSH were significantly decreased, and the trend of increase or decrease in patients with progressive psoriasis was more obvious. The expression of ACSL4, a key regulator of ferroptosis, was significantly increased in psoriatic lesions and further up-regulated in patients with progressive psoriasis. ACSL4 expression was positively correlated with PASI score and the expression levels of inflammatory cytokines (TNF-α, IL-6, IL-8 and IL-17a), and linear regression analysis showed that high expression of ACSL4 in psoriatic lesions was associated with higher PASI score. Both ferroptosis inducer Erastin and IFN-γ/TNF-α significantly induced ferroptosis, inhibited keratinocyte viability, promoted the accumulation of MDA, ROS and Fe²⁺, and enhanced ACSL4, TNF-α, IL-6 and IL-8 expression. When ferroptosis inhibitor Ferrostatin-1 was added to inhibit ferroptosis, the up-regulation trends of MDA, ROS, Fe²⁺, ACSL4, TNF-α, IL-6 and IL-8 were significantly inhibited, and inhibition of ACSL4 expression also had a similar effect. Apoptosis inhibitor Z-VAD-FMK could also attenuate the pro-inflammatory effect of IFN-γ/TNF-α, and Fer-1 plus Z-VAD-FMK further inhibited the expression of inflammatory cytokines. Thus, ferroptosis is significantly activated during the progression of psoriasis and promotes inflammatory responses by upregulating ACSL4 expression. This discovery will provide new targets for clinical detection, prevention and treatment of psoriasis.