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.