Psoriasis represents a classic immune-mediated chronic inflammatory skin disorder with widespread global prevalence. Traditional research frameworks center on the IL-23/Th17 immune cascade to explain bidirectional communication between immune cells and epidermal keratinocytes, while the mechanical regulatory functions of dermal extracellular matrix microenvironment have long been overlooked. A recently proposed mechano-chemical signaling axis starts with dendritic cell-derived galectin-9, which acts on CD44-expressing papillary fibroblasts to trigger excessive collagen deposition and pathological stiffening at the dermal-epidermal junction. Such mechanical tissue alterations further activate downstream intracellular signaling cascades in basal keratinocytes, driving persistent epidermal hyperproliferation via sequential HMGB2 and RRM2 upregulation. Rather than serving as a direct mechanical sensor, HMGB2 acts as a downstream transcriptional effector whose nuclear translocation and expression levels are controlled by matrix stiffness-dependent mechanotransduction signals including YAP/TAZ. This paper systematically dissects the multi-layered molecular logic of this cross-tissue chemical-mechanical signaling circuit and compares its potential conserved pathological roles across atopic dermatitis, systemic sclerosis and cutaneous squamous cell carcinoma. We further summarize major methodological and translational limitations of existing research, such as insufficient age and sex stratification in preclinical and human tissue studies, and the lack of direct in vivo evidence supporting mechanical positive feedback loops in psoriatic lesions. Distinct from conventional single-target anti-cytokine regimens, we put forward a novel dual therapeutic strategy combining anti-inflammatory and localized anti-fibrotic interventions for refractory inflammatory skin diseases, avoiding systemic toxicities caused by broad-spectrum anti-fibrotic agents. Targeting cell-matrix mechanotransduction interfaces provides a promising direction for developing durable treatments for intractable inflammatory dermatoses.

Psoriasis, Mechanobiology, Extracellular matrix stiffness, LGALS9, Fibroblasts, Mechanotransduction