Ferro‐Inflammatory Niches in Psoriatic Lesions Uncover Immune‐Uncoupled IL ‐17 Transcriptional Activity

Ferroptosis-compatible lipid-peroxidation stress has emerged as a psoriasis-relevant epithelial and inflammatory pathway. Whether this activity defines a distinct lesional niche state with selective pathological relevance remains unclear. A systemic ferro-balance analysis first assessed whether circulating immune cells were transcriptionally skewed towards ferroptosis vulnerability or protection, revealing reduced vulnerability in lymphocytes from psoriatic arthritis. An independent spatial transcriptomic analysis then applied the ferroptosis-vulnerability framework, classifying leukocyte-rich inflammatory regions into inflammatory-resilient niches with lower vulnerability and ferro-inflammatory niches with increased vulnerability. Inflammatory-resilient niches expanded in both psoriatic and non-psoriatic skin inflammation, whereas ferro-inflammatory niches were preferentially enriched in psoriatic lesions. Independent layer-resolved mapping confirmed that both states expanded in lesional psoriatic skin, but ferro-inflammatory niches showed stronger epidermal bias. Epidermal ferro-inflammatory burden correlated selectively with IL-17 response-associated transcriptional activity, without parallel coupling to broader immune signatures. This restricted IL-17 programme also tracked clinical severity, while inflammatory-resilient niches lacked comparable severity-linked immune activity. These findings identify epidermal ferro-inflammatory niches as a lesion-enriched tissue state in which IL-17 transcriptional activity is spatially uncoupled from broad immune-signature enrichment, providing a framework to distinguish generic inflammatory expansion from ferroptosis-compatible psoriatic tissue pathology.