Context-dependent short-chain fatty acids in inflammatory skin diseases: Immunometabolic mechanisms, evidence boundaries, and translational perspectives.

Inflammatory skin diseases(ISDs) arise from dynamic interactions among epithelial barrier dysfunction, immune dysregulation, microbial imbalance and metabolic cues. Within gut-skin and skin-microbiome axes, short-chain fatty acids (SCFAs) have attracted attention as microbial metabolites with anti-inflammatory and barrier-regulatory potential. However, treating SCFAs as uniformly beneficial obscures major biological and translational uncertainties. This narrative review synthesizes evidence from mechanistic, preclinical and clinical studies to define how acetate, propionate and butyrate regulate cutaneous immunity and barrier function. SCFAs act through free fatty acid receptors(FFARs), hydroxycarboxylic acid receptor 2(HCAR2), histone deacetylase inhibition(HDAC) and metabolic-substrate effects, but their outcomes depend on species, source, dose, tissue bioavailability, pH, receptor expression, target-cell identity and disease stage. Gut-derived SCFAs are more likely to support systemic immunometabolic regulation and barrier maturation, whereas locally produced cutaneous SCFAs can either maintain microbial and lipid homeostasis or amplify Toll-like receptor-driven inflammation in pilosebaceous niches. We discuss these mechanisms across immune cells, keratinocytes, sebocytes, fibroblasts, adipocytes and endothelial cells, and interpret their relevance to atopic dermatitis, psoriasis, acne vulgaris, rosacea, hidradenitis suppurativa, chronic spontaneous urticaria and contact dermatitis. We further evaluate dietary, prebiotic/probiotic, topical, fecal microbiota transplantation, engineered probiotic, prodrug and delivery-based strategies, distinguishing SCFA-specific causality from broader microbiome remodeling. A context-resolved framework is needed to translate SCFA biology into rational immunometabolic interventions for ISDs.