Rice-Derived Peptides Exhibit Wound Healing Properties in Human Keratinocytes: Screening, Identification, and Mechanism Revelation.

Food-derived biopeptides have attracted increasing attention due to their potential health benefits and favorable safety profiles. In this study, rice protein hydrolysates (< 3 kDa) and their derived peptides were investigated for their protective effects against tumor necrosis factor (TNF)-α/interferon (IFN)-γ-induced injury in human keratinocyte cells (HaCaT). The hydrolysates significantly enhanced cell viability and migration, and five peptides were identified by LC-MS/MS and in-silico analysis. These peptides improved the viability of damaged cells, with PG9 (PSWVAFTGG) showing the greatest activity. PG9 significantly downregulated the mRNA expression of pro-inflammatory cytokines, including Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES), Interleukin (IL)-1β, IL-6, and IL-23, while also markedly promoting keratinocyte migration. Molecular dynamics simulations revealed that PG9 formed stable hydrogen-bonds with key residues (Lys745 and Asp855) within the epidermal growth factor receptor (EGFR) binding site, suggesting its involvement in EGFR-mediated wound healing signaling. In addition, PG9 regulated the PI3K/AKT/mTOR pathway by reducing the expression of PI3K, AKT, mTOR, and inhibiting AKT phosphorylation. These results identify PG9 as a stable EGFR-binding peptide capable of modulating inflammatory signaling and supporting its potential as a natural agent for skin repair.