Lights and Shadows of Nutrient-Driven Keratinocyte Inflammation in Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation, impaired differentiation, and dysregulated immune responses. Emerging evidence highlights the central role of keratinocytes as immune-competent cells that integrate signals from cytokines, metabolic cues, the gut–skin axis, and the tissue microenvironment. Key intracellular signaling pathways, including NF-κB, JAK/STAT, MAPK, and PI3K/AKT/mTOR, along with the IL-23/IL-17 axis, orchestrate keratinocyte-mediated inflammation and epidermal hyperplasia. Metabolic factors, nutrients, and redox balance further modulate these responses, while the intestinal microbiota and its metabolites, such as short-chain fatty acids, shape systemic and cutaneous inflammation. This review offers a critical, integrated perspective, that moves beyond descriptive summaries. We propose a conceptual framework in which the keratinocyte metabolic state, particularly the sirtuin/NAD+ axis, acts as a crucial convergence point for systemic nutritional, microbial, and inflammatory signals. Targeting sirtuins and associated pathways with natural or synthetic modulators represents a promising, host-centric strategy to restore keratinocyte function and reduce chronic inflammation. This synthesis underscores the potential of combining molecular, metabolic, microbial, and nutritional insights to develop personalized and effective approaches for psoriasis management.