| Summary: | 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 (<i>CYP1A1</i>) 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 (<i>SKP2</i>) and serine- and arginine-rich splicing factor 5 (<i>SRSF5</i>) were the top upregulated genes in cell cycle and spliceosome pathways, respectively. Indirect immunofluorescent cytochemistry confirmed increased protein levels of <i>CYP1A1</i>, <i>SKP2</i>, and <i>SRSF5</i> after L-Arginine treatment. Knockdown of <i>CYP1A1</i>, <i>SKP2</i>, and <i>SRSF5</i> 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 <i>CYP1A1</i>, <i>SKP2</i>, and <i>SRSF5</i>, suggesting that supplemental L-Arginine in oral care products may be beneficial for oral tissue repair and regeneration.
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