This manuscript investigates the mechanistic effects of the cyclic hexapeptide CP161 on human dermal fibroblasts exposed to UV irradiation, emphasizing its role in preserving extracellular matrix homeostasis and mitigating fibroblast senescence. By elucidating the direct interaction between CP161 and MAP2K1, as well as its downstream impact on the MEK1/2–ERK1/2 signaling cascade, this study contributes to a deeper understanding of skin physiology, particularly in response to environmental stressors.