Core Viewpoint - The research highlights the evolutionary adaptation mechanisms in skin that support terrestrial locomotion, particularly focusing on the role of the SLURP1 gene in preventing palmoplantar keratoderma (PPK) [2][3]. Group 1: Evolutionary Mechanisms - The transition from aquatic to terrestrial life required vertebrates to overcome significant physiological and biomechanical challenges, with skin structure being crucial for this adaptation [2]. - The study published in Cell reveals a mechano-resistance mechanism in skin that adapts to the mechanical stresses of land locomotion [2][5]. Group 2: SLURP1 Gene and PPK - The SLURP1 gene is specifically expressed in the skin of the palms and soles of four-legged animals, and mutations in this gene in humans lead to PPK, characterized by excessive thickening and cracking of the skin [3][6]. - In SLURP1 knockout mice, reducing mechanical stress on the paw skin completely reverses the PPK phenotype, indicating the gene's critical role in skin health [3][6]. Group 3: Mechanistic Insights - SLURP1 protein is located in the endoplasmic reticulum (ER) membrane and interacts with the calcium pump SERCA2b, maintaining calcium levels under mechanical stress [3][6]. - By regulating the activity of SERCA2b, SLURP1 prevents the activation of the pPERK-NRF2 signaling pathway, which is associated with PPK, thus maintaining epidermal homeostasis [3][6].