Lipoic acid synthase modulates psoriasis-like keratinocyte dysfunction in association with oxidative stress,...

Psoriasis is a complex inflammatory disease associated with keratinocyte hyperproliferation, abnormal differentiation, and hyper-inflammation. Recent advances have indicated that oxidative stress and ferroptosis contribute to the development of this pathology; however, the regulation of their mechanisms remains unclear. This research aimed to reveal the impact of lipoic acid synthase (LIAS), a mitochondrial enzyme that is critical for redox regulation, on psoriasis-like keratinocytes. LIAS expression was significantly upregulated upon stimulation of HaCaT cells with TNF-α and IL-17A at both transcriptional and translational levels. It was found that LIAS expression led to cell proliferation, migration, and pro-inflammatory cytokines production while silencing of LIAS gene inhibited these processes. Additionally, overexpression of LIAS led to an increase in intracellular ROS generation, oxidative damage, and mitochondrial dysfunction revealed by elevated mitochondrial ROS generation and reduced mitochondrial membrane potential. Moreover, LIAS influenced ferroptosis-related markers, such as GPX4, ACSL4, and FTH1. LIAS overexpression was also associated with increased activation of STAT3 and NF-κB signaling, consistent with enhanced inflammatory signaling. Moreover, LIAS inhibited keratinocyte differentiation revealed by the elevation of KRT16 expression and decreased expression of involucrin, filaggrin, and loricrin. Importantly, N-acetylcysteine and ferrostatin-1 significantly suppressed LIAS-induced effects. These results collectively identify LIAS as a regulator of psoriasis-like keratinocyte dysfunction and indicate that its effects are associated with oxidative stress, ferroptosis-related molecular remodeling, and inflammatory signaling. These findings suggest that LIAS-associated mitochondrial and redox signaling warrants further investigation in psoriasis pathogenesis.