NUCB2/Nesfatin-1 Couples Cholesterol Biosynthesis to Keratinocyte Migration to Accelerate Re-Epithelialisation in Cutaneous Wound Repair.

Delayed re-epithelialisation is a key feature of chronic and recurrent cutaneous wounds, but the metabolic mechanisms that coordinate keratinocyte migration and epidermal barrier restoration remain incompletely defined. Here, we investigated whether NUCB2/Nesfatin-1 regulates keratinocyte-driven wound repair through cholesterol biosynthesis. Transcriptomic profiling revealed coordinated downregulation of cholesterol biosynthetic genes in NUCB2-deficient keratinocytes. Concurrently, gene signatures associated with cell motility and epithelial plasticity were also suppressed. Functionally, NUCB2 depletion impaired CCK-8-based metabolic/proliferative activity, scratch-wound closure, Transwell migration and epithelial marker expression, whereas exogenous Nesfatin-1 partially restored these defects. Mechanistic analyses showed that NUCB2/Nesfatin-1 enhanced mTORC1 downstream signalling, increased nuclear SREBP2 abundance and HMGCR expression, and promoted intracellular cholesterol accumulation. Cholesterol supplementation or HMGCR overexpression partially restored cholesterol availability and migratory capacity in NUCB2-deficient keratinocytes, whereas rapamycin attenuated Nesfatin-1-associated SREBP2-HMGCR induction, cholesterol accumulation and migration. In a murine full-thickness excisional wound model, local Nesfatin-1 administration accelerated wound closure and enhanced early re-epithelialisation, accompanied by increased SREBP2 and HMGCR expression at the wound-edge epidermis. Complementary local Nucb2 silencing delayed wound closure. These findings define a NUCB2/Nesfatin-1-mTORC1 downstream signalling-SREBP2-HMGCR axis that supports cholesterol-dependent keratinocyte migration and epidermal repair.