ORIGINAL RESEARCH article
Front. Pediatr.
Sec. Genetics of Common and Rare Diseases
Volume 13 - 2025 | doi: 10.3389/fped.2025.1632778
This article is part of the Research TopicInsights in Genetics of Common and Rare Diseases 2024View all 28 articles
Oxidative Stress-Mediated Apoptosis via SLC23A2-Ascorbic Acid Interaction Contributes to Cleft Lip Development
Provisionally accepted
- Nanjing Stomatological Hospital Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
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Objectives: Non-syndromic cleft lip only (NSCLO) is a common subtype of cleft lip with/without cleft palate (CL/P). Previously, we found that SLC23A2 is closely related to cleft palate through gene-environment interaction studies, but whether SLC23A2 is related to cleft lip has not been reported. Design: Firstly, the genotyping data of SNPs at SLC23A2 in 1047 patients with NSCLO and 2255 normal controls were extracted from two previous GWAS for association analysis. Then, the effect of SLC23A2, reactive oxygen species(ROS) and ascorbic acid(AA) interaction on oxidative stress and apoptosis level of GMSM-K cell line and zebrafish was verified in vitro and vivo. Finally, the mechanism of SLC23A2 involved in the occurrence of cleft lip was initially explored by RNA-seq. Results: Association analysis showed that 10 SNPs located at SLC23A2 were significantly correlated with NSCLO. In vitro experiments have showed that knockdown of SLC23A2 in GMSM-K inhibits the expression of COL9A3 in PI3K-Akt signaling pathway, promoting the increase of ROS, and triggering increased apoptosis. The interaction results showed that ROS and apoptosis level of GMSM-K with normal SLC23A2 gene function stimulated by Sin-1(exogenous ROS mimics) increased, and ROS and apoptosis level can be reduced by AA supplementation. Knocked down SLC23A2 in GMSM-K cells, they became more sensitive to Sin-1, and AA supplementation was ineffective. In addition, increased ROS and apoptosis level were also observed in slc23a2-MO zebrafish, which could not be rescued by AA supplementation. Conclusion: SLC23A2 was significantly associated with NSCLO. SLC23A2/ exogenous ROS/AA interaction was involved in lip and craniofacial development by influencing the level of ROS and apoptosis. Keywords: Non-syndromic cleft lip only; Association analysis; Reactive oxygen species; Gene-environment interaction; Apoptosis
Keywords: Non-syndromic cleft lip only, association analysis, Reactive Oxygen Species, gene-environment interaction, Apoptosis
Received: 21 May 2025; Accepted: 29 Aug 2025.
Copyright: © 2025 Yin, Xu and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yong Lu, Nanjing Stomatological Hospital Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
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