Long‐Term Human Skin Platform for Modeling Chronic Inflammation, Environmental Stress, and Therapeutic Intervention

Chronic inflammation drives tissue dysfunction and aging, yet the dynamic interplay between persistent inflammatory signaling and structural deterioration remains difficult to study in human-relevant systems. Here, an advanced long-term human skin platform is presented that preserves native tissue architecture and epidermal, stromal, and immune-associated molecular programs for up to 4 weeks. Time-course RNA sequencing of 199 tissue samples from 20 donors revealed an early culture adaptation phase followed by stabilization of tissue-associated transcriptional programs. Using this system, sustained IL-17/IL-22 stimulation over 3 weeks induced chronic inflammatory transcriptional programs, progressive histopathological changes, and persistent secretion of IL-8, MCP-1, S100A8/A9, and MMP-1, which was broadly suppressed by the Janus kinase inhibitor tofacitinib. In aged donor tissue, prolonged senolytic-associated treatment attenuated inflammatory and remodeling pathways and reduced senescence-associated secretory factors, including IL-6 and MMP-1, with significant treatment-associated effects evident at Week 3 but not Week 1. Finally, ultraviolet B exposure triggered coordinated stress and inflammatory responses that were mitigated using topical sunscreen, demonstrating compatibility with environmental stress modeling and topical intervention. Together, these findings establish a versatile human skin platform for modeling chronic inflammation, aging-associated tissue remodeling, and environmental stress, providing a translational framework for investigating skin tissue dysfunction and evaluating therapeutic interventions.