<p>Skin inflammation could induce various skin diseases. Anti-inflammatory peptides have been widely employed in treating skin problems due to their excellent therapeutic effects without inducing significant side effects. In our previous study, six anti-inflammatory peptides were screened from yak bone collagen. However, their effects on skin inflammation have not been investigated. To further expand the application fields of yak bone collagen-derived peptides, the effects and mechanisms of the screened anti-inflammatory peptide were studied based on the lipopolysaccharide-induced HaCaT cell inflammation model. Moreover, the stability of peptide under various environmental factors was detected to evaluate its application potential. At the concentration of 100 µM, the inhibitory rate of GPAGPSGPAGKDGR(Seq2) on IL-6, IL-1β, TNF- α and NO was 85.71 ± 1.40%, 78.10 ± 4.02%, 80.60 ± 1.34% and 94.79 ± 0.48%, respectively. Compared with the model group, the p-P65/t-P65 ratio and the p-IκB/t-IκB ratio in HaCaT cells of the Seq2 treatment group reduced approximately 32.11% and 39.39%, respectively. In addition, Seq2 exhibited a good thermal stability below 50 ℃. The pH, light, metal ions, and typical processing aids have almost no significant influences on the stability of Seq2, it kept around 90% of its initial concentration under a certain range of these factors. These results indicated that the yak bone collagen-derived peptide Seq2 with excellent stability improves inflammation in HaCaT cells by regulating the NF-κB signaling pathway. Our study would broaden the exploration of food-derived anti-inflammatory peptides and provide new directions for further research on yak bone derived proteins.</p> Graphical abstract <p></p>