精神分裂症（SCZ）的发病机制很大程度上受遗传因素影响。人们认为环指蛋白 4 (RNF4) 和 T 细胞识别的鳞状细胞癌抗原 3 (SART3) 通过氧化应激途径参与神经系统的生长和发育。此外，他们此前曾与 SCZ 有联系。然而 RNF4 和 SART3 在 SCZ 中的作用仍不清楚。在这里，我们通过研究在患者中观察到的这两个基因的变异来研究这两个基因如何参与 SCZ。我们首先观察到与对照组 (n = 60) 相比，首发 (n = 30) 和慢性 (n = 30) SCZ 患者外周血中 RNF4 和 SART3 mRNA 水平显着升高。接下来，我们使用从 SCZ 参与者 (n = 392) 和对照 (n = 572) 的外周血白细胞中提取的基因组 DNA，对 SART3 中的 3 个单核苷酸多态性 (SNP) 和 RNF4 中的 6 个 SNP 进行靶向测序，以与 SCZ 相关。我们观察到包括 rs1203860、rs2282765（均在 RNF4 中）和 rs2287550（在 SART3 中）在内的 SNP 组合与 SCZ 风险增加相关，表明这两个基因之间存在共同的致病机制。然后我们在 HEK293T 细胞中进行了实验，以更好地了解 RNF4 和 SART3 之间的相互作用。我们观察到SART3通过泛素化降低RNF4的表达，并下调RNF4下游因子核因子E2相关因子2（NRF2）的表达，暗示RNF4和SART3可能存在共同的调控机制。总之，我们的研究提供了证据表明 RNF4 和 SART3 之间的相互作用会增加 SCZ 的风险。这些发现揭示了 SCZ 的潜在分子机制，并可能导致针对这种疾病的新疗法和干预措施的开发。© 2024 由 Elsevier Ltd 出版。

The pathogenesis of schizophrenia (SCZ) is heavily influenced by genetic factors. Ring finger protein 4 (RNF4) and squamous cell carcinoma antigen recognized by T cells 3 (SART3) are thought to be involved in nervous system growth and development via oxidative stress pathways. Moreover, they have previously been linked to SCZ. Yet the role of RNF4 and SART3 in SCZ remains unclear. Here, we investigated how these two genes are involved in SCZ by studying their variants observed in patients. We first observed significantly elevated mRNA levels of RNF4 and SART3 in the peripheral blood in both first-episode (n = 30) and chronic (n = 30) SCZ patients compared to controls (n = 60). Next, we targeted-sequenced three single nucleotide polymorphisms (SNPs) in SART3 and six SNPs in RNF4 for association with SCZ using the genomic DNA extracted from peripheral blood leukocytes from SCZ participants (n = 392) and controls (n = 572). We observed a combination of SNPs that included rs1203860, rs2282765 (both in RNF4), and rs2287550 (in SART3) was associated with increased risk of SCZ, suggesting common pathogenic mechanisms between these two genes. We then conducted experiments in HEK293T cells to better understand the interaction between RNF4 and SART3. We observed that SART3 lowered the expression of RNF4 through ubiquitination and downregulated the expression of nuclear factor E2-related factor 2 (NRF2), a downstream factor of RNF4, implicating the existence of a possible shared regulatory mechanism for RNF4 and SART3. In conclusion, our study provides evidence that the interaction between RNF4 and SART3 contributes to the risk of SCZ. The findings shed light on the underlying molecular mechanisms of SCZ and may lead to the development of new therapies and interventions for this disorder.© 2024 Published by Elsevier Ltd.