<i>Diospyros lotus</i> leaf extract and its main component, myricitrin, inhibit both histamine‑dependent and histamine‑independent itching

Pruritus is a distressing symptom associated with various dermatological, systemic and neurological conditions, markedly impairing quality of life. Pruritus arises through histamine-dependent and histamine-independent pathways, involving mediators such as histamine, gastrin-releasing peptide (GRP), interleukin-31 (IL-31) and STAT3 signaling. The present study aimed to investigate the antipruritic effects of <i>Diospyros lotus</i> leaf extract (DLE) and its major constituent, myricitrin (MC), on ICR mice using compound 48/80 (histamine-dependent) and chloroquine (histamine-independent) itch models. Serum levels of histamine and IL-31 were measured by ELISA, and mast cell infiltration was assessed via toluidine blue staining. Furthermore, the expression and activation of GRP receptor (GRPR), IL-31RA and STAT3 in the spinal cord were analyzed using western blotting and immunofluorescence staining. Notably, DLE and MC significantly reduced scratching behavior, serum histamine levels and mast cell infiltration in both models. Immunofluorescence staining and western blot analysis revealed that DLE and MC downregulated GRPR, IL-31 receptor A and phosphorylated STAT3 expression in the spinal cord, indicating modulation of central itch signaling. Additionally, DLE and MC suppressed IL-31 levels in serum and skin tissues. These findings indicated that DLE and MC may alleviate pruritus through multiple mechanisms, including mast cell stabilization, histamine reduction and modulation of central itch pathways. The broad-spectrum antipruritic activity of DLE and MC highlights their potential as natural therapeutic agents for diverse pruritic conditions, offering a safer alternative to synthetic antipruritic drugs. Further research is warranted to validate these findings in clinical settings and to elucidate the molecular mechanisms underlying their efficacy.