Abstract

The utility of silk protein spans from East Asian traditions to promising applications in modern biomaterials science. While its bioactive effect is widely accepted, its molecular mechanisms and the supporting data have remained elusive. This study reveals the anti-photoaging mechanism of silk protein enzymatic hydrolysate (SEH), identifying key peptides SO1 from silk seroin and SC1 from silk sericin. Mechanistically, SO1 targets PDGFRβ to inhibit the NF-κB/ERK/SASP cellular senescence axis, while SC1 targets TRPV4 to suppress MITF-driven melanin synthesis. Additionally, the SO1 and SC1 combination suppresses key hallmarks of photoaging. It reduced senescence, confirmed by diminished β-galactosidase activity and SASP, while concurrently mitigating oxidative stress and hyperpigmentation, and promoting cell migration. Further network pharmacology analysis reveals a multi-component interaction network connecting bioactive silk peptides, target receptors, and downstream signaling pathways involved in mitigating photoaging. This integrative mechanism was defined as the “Silk Peptides Mesh”, with SO1 and SC1 identified as representative core peptides within this system. Finally, a 28-d skin clinical trial involving 30 participants confirms these findings, showing that a cream containing SO1 and SC1 improves photoaging-related skin indicators. Importantly, this work establishes a paradigm shift from conventional single-molecule approaches to a multi-component network understanding of bioactive peptide functionality.