Disulfiram Attenuates Psoriasis Progression by Modulating the States of Keratinocytes and Ly6C hi Monocytes: An Exploratory Study

Objective: Psoriasis is a chronic inflammatory skin disease driven by dysregulated immune responses and keratinocyte activation. How topical disulfiram (DSF) ameliorates imiquimod-induced psoriatic dermatitis beyond pyroptosis inhibition remains unclear. This study aims to elucidate its cellular and molecular mechanisms and assess its multi‑target therapeutic potential. Methods: A murine model was established with petroleum jelly, imiquimod, and DSF treatment groups. Single-cell RNA sequencing of dorsal skin was performed to construct a cellular atlas. Bioinformatic analyses were conducted to identify key DSF-responsive populations. Findings were validated by flow cytometry, histology, and enzyme-linked immunosorbent assay. The role of Ly6C hi monocytes was evaluated using a selective C-C chemokine receptor type 2 (CCR2) inhibitor. Network pharmacology and molecular docking analyses were conducted to predict multi-target mechanisms. Results: Keratinocytes and myeloid cells were identified as central targets. DSF suppressed the expansion of a pathogenic keratinocyte subtype (Epd_DF2) and inhibited psoriasis-associated proinflammatory and metabolic pathways. DSF altered the functional activation state of Ly6C hi monocytes without affecting their abundance. In T cells, DSF attenuated IL-23/IL-17 axis activation, as reflected by reduced Il17a and Il17f expression and increased inhibitory signatures. CCR2 inhibition attenuated disease severity, reduced serum IL-17A levels, and significantly decreased Ly6C hi monocyte proportions from 23.6% ± 1.8% in the IMQ group and 23.3% ± 2.2% in the IMQ+Vehicle group to 13.9% ± 1.8% in the IMQ+BMS group ( F = 8.18, P = 0.003), whereas the VAS group showed a baseline proportion of 15.1% ± 6.4%, without altering neutrophil abundance. Multi-target analysis predicted mTOR and NQO1 as potential targets. Conclusion: Topical DSF ameliorates psoriasiform inflammation through multi-target effects on keratinocyte differentiation and immune cell function, accompanied by modulation of the IL-17A axis and CCL2/CCR2-related signaling. These findings support the potential repurposing of DSF as a nonsteroidal topical therapy for psoriasis.