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Diabetic ulcers, a serious complication associated with diabetes, present a significant therapeutic challenge due to their recurrent and persistent chronic inflammation. A crucial factor contributing to this sustained inflammation is mast cell degranulation. This study examined the effects of the traditional Chinese herbal formula Zizhu ointment (ZZO) on mast cell degranulation in diabetic ulcers, as well as its underlying mechanisms in promoting wound healing. Analysis of clinical specimens revealed that ZZO significantly inhibited mast cell degranulation in diabetic ulcer wounds. In a diabetic mouse wound model, ZZO was observed to suppress mast cell degranulation, decrease the expression of TNF-α and MMP-9, and facilitate wound healing. Cellular experiments demonstrated that ZZO inhibited IgE/DNP cross-linking-mediated degranulation, calcium (Ca²⁺) influx, and the release of β-hexosaminidase, histamine (HIS), and TNF-α in both human HMC-1 and murine P815 mast cells. Furthermore, ZZO was found to block the IgE/DNP cross-linking-mediated activation of FcεRI-proximal signaling pathways (LYN/SYK/PLCγ) and inflammatory cascades (IKK/NFκB and MAPKs). We hypothesize that ZZO facilitates the healing of diabetic ulcers by stabilizing mast cells and inhibiting their degranulation, thereby reducing the release of inflammatory mediators and promoting wound repair.