Ac EL-6 Reduces Methylglyoxal-Associated Glycation and NF-κB-Mediated Inflammatory Responses While Supporting Acute Skin Repair

Purpose Advanced glycation end products (AGEs) and their downstream inflammatory consequences contribute to skin dysfunction and aging-related deterioration. EQ-9 has been identified as a novel functional peptide with anti-aging and skin repair potential. In this study, we investigated the effects of EQ-9 and its two derivatives (EL-6 and ac EL-6) on Methylglyoxal (MGO)-induced glycation and inflammatory damage. Methods We exposed HaCaT cells to MGO to simulate hyperglycemic conditions. The protective effects of these peptides were assessed through measurements of cell viability, migration, CML levels, inflammatory cytokine secretion, RAGE expression, and NF-κB pathway activation. Additionally, TNF-α/IFN-γ were used to induce inflammatory injury and evaluate the anti-inflammatory effectiveness of the peptides. A murine excision wound model was also established to examine the effects of ac EL-6 on skin inflammation, collagen deposition, angiogenesis, and wound healing. Results All three peptides significantly reduced MGO-induced CML generation, downregulated RAGE, inhibited NF-κB activation, attenuated proinflammatory cytokine secretion, alleviated cell damage, and promoted migration. They also mitigated TNF-α/IFN-γ-evoked inflammatory responses via NF-κB suppression. Topical application of ac EL-6 decreased cytokine levels, increased VEGF expression and collagen deposition, and consequently accelerated wound healing in mice. Conclusion Together, these findings identify ac EL-6 as a stabilized lead candidate derived from EQ-9, which exhibits anti-glycation activity and modulates NF-κB-mediated inflammatory signaling in keratinocytes, and demonstrates initial skin-repair potential in vivo. The data support further development of ac EL-6 for skin-directed applications. Graphical