{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:09:13Z","timestamp":1793664553698,"version":"4.5.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Non-syndromic cleft lip only (NSCLO) is a common subtype of cleft lip with\/without cleft palate (CL\/P). Previously, we found that <jats:italic>SLC23A2<\/jats:italic> is closely related to the occurrence of cleft palate through gene\u2013environment interaction studies, but whether <jats:italic>SLC23A2<\/jats:italic> is related to the occurrence of cleft lip has not been reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>First, the genotyping data of single-nucleotide polymorphisms (SNPs) at <jats:italic>SLC23A2<\/jats:italic> in 1,047 patients with NSCLO and 2,255 normal controls were extracted from two previous genome-wide association studies (GWASs) for an association analysis. Then, the interaction effect of <jats:italic>SLC23A2<\/jats:italic>, reactive oxygen species (ROS), and ascorbic acid (AA) on oxidative stress and apoptosis levels in the human oral epithelial-derived cell line (GMSM-K) and zebrafish was verified <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Finally, the mechanism of how <jats:italic>SLC23A2<\/jats:italic> is involved in the occurrence of cleft lip was initially explored using RNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The association analysis showed that 10 SNPs located at <jats:italic>SLC23A2<\/jats:italic> were significantly correlated with NSCLO. <jats:italic>In vitro<\/jats:italic> experiments have shown that knockdown of <jats:italic>SLC23A2<\/jats:italic> in GMSM-K inhibits the expression of <jats:italic>COL9A3<\/jats:italic> in the PI3K-Akt signaling pathway, promoting an increase in ROS and triggering increased apoptosis. The interaction results showed that the ROS and apoptosis levels increased in GMSM-K cells with normal <jats:italic>SLC23A2<\/jats:italic> gene function when stimulated by Sin-1 (exogenous ROS mimics) and ROS and apoptosis levels can be reduced by AA supplementation. GMSM-K cells became more sensitive to Sin-1, and AA supplementation was ineffective after <jats:italic>SLC23A2<\/jats:italic> knockdown. In addition, increased ROS and apoptosis levels were also observed in <jats:italic>slc23a2-MO<\/jats:italic> zebrafish, and could not be rescued by AA supplementation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>SLC23A2<\/jats:italic> was significantly associated with NSCLO. The <jats:italic>SLC23A2<\/jats:italic>\/exogenous ROS\/AA interaction is involved in lip and craniofacial development by influencing the levels of ROS and apoptosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2025.1632778","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T04:21:12Z","timestamp":1759378872000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Oxidative stress-mediated apoptosis via the SLC23A2-ascorbic acid interaction contributes to cleft lip development"],"prefix":"10.3389","volume":"13","author":[{"given":"Bin","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi 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