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.

Chondrocytes maintain cartilage integrity through coordinated regulation of extracellular matrix (ECM) synthesis and remodeling. These processes depend on ECM dynamic interactions, mediated by integrin-based focal adhesions and associated cytoskeletal components. While the roles of core adhesion proteins are well described, the involvement of sarcoglycans (SGs) remains unclear in chondrocytes. Drawing parallels from striated muscle, where the SG subcomplex stabilizes the sarcolemma, we hypothesized that SGs similarly integrate into chondrocyte adhesion complexes. This study investigated the SGs (α, β, γ, δ) expression with cytoskeletal and adhesion proteins, including actin and vinculin, in human chondrocytes cultured by immunofluorescence, qPCR, and siRNA-mediated silencing. All four SG isoforms were expressed in the cytoplasmic and membrane domains, with enrichment at focal adhesion sites. Double labeling revealed SG colocalization with F-actin stress fibers and vinculin, indicating integration into the core adhesion complex. Silencing of each SG resulted in disrupted actin stress fibers, diffuse vinculin distribution, reduced focal plaque number, and a change in cell morphology. These findings support the hypothesis that SGs regulate actin cytoskeletal dynamics and focal contact stabilization. Loss of SG function compromises chondrocyte shape and adhesion, highlighting the importance of these glycoproteins also in non-muscle cells.

Endocan, a soluble dermatan sulfate proteoglycan, is increasingly recognized as a regulator of key cellular pathways in both physiological and pathological contexts. While TGF-β is a central mediator of fibrotic remodeling, the role of endocan in this process remains elusive. By performing a transcriptomic dataset analysis [GSE116250], we found that endocan expression is upregulated and correlates with fibrotic markers in human failing hearts. We investigated the role of endocan in an in vitro model of cardiac fibroblasts stimulated with TGF-β. Our results identified endocan as a TGF-β-responsive gene in primary human cardiac fibroblasts. Indeed, by inhibiting endocan expression using a specific siRNA, we demonstrated that this proteoglycan is required for the full expression of key fibrosis-related genes (Col1a1, α-SMA, MMP-3, and MMP-9) and modulates the expression of long non-coding RNAs (MALAT1, H19 and HOTAIR), which are essential for the epigenetic control of the fibroblast phenotype. These effects depend on the modulation of both canonical (SMAD3) and non-canonical (AKT and ERK1/2) TGF-β pathways. Taken together, these findings indicate that endocan is required for the coordinated activation of canonical and non-canonical TGF-β signaling during fibroblast transdifferentiation and suggest its potential involvement in the molecular mechanisms underlying cardiac fibrosis.