Psoriatic lesions show an epidermal transcriptional pattern liking lactate-associated niche-state imbalance with hypoxia-regulatory activity.

Lactate handling sits at the interface of glycolytic stress, hypoxia and immune regulation in inflamed skin. However, the tissue and immune contexts in which these lactate-associated features are embedded in psoriatic lesions remain poorly defined. To resolve this organisation, spatial transcriptomics mapped lactate-associated transcriptional inflammatory states, separating lactate-disconnected niches, defined by inflammation without lactate-handling transcriptional activity, from lactate-coupled niches, marked by coordinated lactate-handling and inflammatory transcriptional activity. This framework revealed increased lactate-handling transcriptional activity in psoriatic skin lesions, but not in non-psoriatic inflammatory lesions, with lactate-coupled niches showing the strongest psoriatic lesion enrichment and association with monocyte/macrophage and dendritic cell activity. Independent layer-resolved analysis confirmed lactate-coupled expansion in lesional psoriatic skin. Although cell-lineage associations differed between dermis and epidermis, lactate-coupled burden was linked to IL-10 transcriptional activity in both compartments, alongside TGF-β activity in the dermis and hypoxia and antigen presenting cell maturation in the epidermis. Clinical severity further refined this pattern, identifying an epidermal lactate-niche imbalance linked to hypoxia activity and regulatory-associated programmes. Peripheral CITE-seq identified psoriatic disease subgroup-specific enrichment of lactate-coupled mononuclear myeloid states and activation markers. These findings define an epidermal lactate niche-state imbalance in psoriatic severity, with the independent peripheral blood cohort showing a directionally similar increase in lactate-coupled myeloid activation.