Fascia-integrated functional mapping of ion channels promotes scar-tapered repair

Fascia has recently been identified as a primary source of wound fibroblasts and scar tissue in deep wound healing models, highlighting the need to explore fascia-centric mechanisms for regenerative therapy. This study aims to systematically evaluate the role of ion channels in fascia contraction and fibroblast activation and their impact on wound healing to identify potential ion channel-targeting compounds that promote scar-reducing healing. We screened a library of 314 ion channel-targeting compounds using live fascia explants undergoing contraction. Hits were further verified by assessing their effects on fascia fibroblast differentiation into proinflammatory (PDPN⁺) and myofibroblast (RUNX2⁺) states. RNA sequencing of sorted CD26⁺ fascia fibroblasts was used to explore downstream regulatory pathways. Finally, therapeutic candidates were tested in a full-thickness excisional wound model in mice. We identified 7 ion channel types with potential therapeutic effects, along with 19 ion channel types and associated pathways showing no effect on fibroblast differentiation. Notably, tariquidar, terfenadine, and zinc pyrithione inhibited the transition from proinflammatory fibroblasts to proto-myofibroblasts. Among them, zinc pyrithione significantly reduced scar formation in vivo. This study provides a functional map of 26 ion channel types in fascia fibroblasts and reveals promising modulators that may advance scar-reducing therapies for deep wound healing.