Disulfiram and Zinc in Neurogenic Rosacea: A Mechanistic Hypothesis Targeting CREB-Mediated Transcriptional Amplification

Rosacea affects approximately 5% of adults worldwide, yet patients with prominent neurogenic features remain refractory to therapies targeting inflammation or vasomotor tone. Converging molecular and clinical evidence positions Substance P–driven neuroimmune signalling as a primary pathogenic axis in these individuals. Substance P activates the NK‑1 receptor, initiating a Gs–adenylate cyclase–cAMP cascade culminating in CREB phosphorylation and transcriptional amplification of cytokines, chemokines, adhesion molecules, and neuropeptides. This amplification step transforms transient neuropeptide release into a self‑sustaining inflammatory state. We advance the hypothesis that disulfiram administered with zinc—a combination previously shown to inhibit ATF/CREB DNA binding via metal‑potentiated covalent modification of conserved bZIP cysteines—can attenuate this transcriptional amplification. Copper is the most potent mechanistic cofactor, but zinc is preferred clinically due to its favourable safety profile. The mechanism is orthogonal to existing rosacea therapies: rather than targeting receptors or inflammatory mediators, it reduces the transcriptional gain that sustains the neurogenic feedback loop. We further formalise neurogenic rosacea as a destabilised positive‑feedback control system. Substance P release, mast‑cell activation, PAR‑2 signalling, and CREB‑dependent transcription constitute a loop whose gain exceeds unity, producing chronic inflammation independent of external triggers. CREB functions as the loop’s amplification node; disulfiram–zinc represents a gain‑reducing intervention capable of restoring stability. Quantitative pharmacokinetic and biochemical data support plausibility: clinically achievable disulfiram metabolite concentrations overlap with the CREB‑inhibitory range, cutaneous zinc levels exceed plasma concentrations, and CREB‑dependent transcription in neuroimmune cells operates at thresholds susceptible to DNA‑binding inhibition. A critical empirical gap remains: CREB inhibition by disulfiram–zinc has been demonstrated only in melanoma cells, not in mast cells, keratinocytes, or sensory neurones. Nonetheless, the mechanistic coherence, quantitative feasibility, and unmet clinical need justify formal investigation. We outline a programme of in vitro, in vivo, and early‑phase clinical studies to evaluate disulfiram–zinc as a targeted modulator of neurogenic inflammation in treatment‑refractory rosacea.