L-Arginine Enhances Oral Keratinocyte Proliferation under High-Glucose Conditions via Upregulation of CYP1A1 , SKP2 , and SRSF5 .

High glucose inhibits oral keratinocyte proliferation. Diabetes can lead to delayed oral wound healing and periodontal disease. L-Arginine, one of the most versatile amino acids, plays an important role in wound healing, organ maturation, and development. In this study, L-Arginine was found to enhance oral keratinocyte proliferation under high-glucose conditions. RNA sequencing analysis discovered a significant number of genes differentially upregulated following L-Arginine treatment under high-glucose conditions. Cytochrome P450 family 1 subfamily A member 1 ( CYP1A1 ) was the most significantly upregulated gene at 24 and 48 h after L-Arginine treatment. Gene Ontology enrichment analysis found that cell proliferation- and mitosis-related biological processes, such as mitotic nuclear division, mRNA processing, and positive regulation of cell cycle processes, were significantly upregulated. Pathway enrichment analysis found that S-phase kinase-associated protein 2 ( SKP2 ) and serine- and arginine-rich splicing factor 5 ( SRSF5 ) were the top upregulated genes in cell cycle and spliceosome pathways, respectively. Indirect immunofluorescent cytochemistry confirmed increased protein levels of CYP1A1 , SKP2 , and SRSF5 after L-Arginine treatment. Knockdown of CYP1A1 , SKP2 , and SRSF5 abolished the enhanced proliferative effect of L-Arginine on oral keratinocytes under high-glucose conditions. In conclusion, L-Arginine enhances oral keratinocyte proliferation under high-glucose conditions via upregulation of CYP1A1 , SKP2 , and SRSF5 , suggesting that supplemental L-Arginine in oral care products may be beneficial for oral tissue repair and regeneration.