Identification of SLC7A1 as a potential therapeutic target for high-grade meningioma

Abstract High-grade meningioma remains a therapeutic challenge. The first-line guideline drugs for high-grade meningioma are still lacking, highlighting the urgent need to uncover new therapeutic targets. As a cationic amino acid transporter, SLC7A1 was highly expressed in high-grade meningioma and associated with poor prognosis of patients. In this study, transcriptomic analyses at both the single-cell and bulk levels were employed to investigate the molecular function of SLC7A1. The Genomics of Drug Sensitivity in Cancer (GDSC) database was utilized for predicting potential drugs targeting high-SLC7A1 meningiomas. RNA sequencing was conducted to explore the differential activity of cancer hallmark pathways and transcription factors. The effects of SLC7A1 knockdown and drug treatment were validated in vitro and in vivo. Our results revealed that SLC7A1 regulates multiple signaling pathways involved in tumor proliferation, including E2F targets, G2M checkpoint, and MYC targets. Knockdown of SLC7A1 significantly inhibited the proliferation, invasion, and xenograft tumor growth of meningioma cells. Furthermore, SLC7A1-FOXM1/E2F4 regulatory axis may contribute to the malignant progression of meningioma. AZ628, predicted as a small molecule drug targeting high-SLC7A1 meningiomas, exhibited an excellent antitumor effect against meningioma in vitro, in vivo, and in organoid models. Additionally, AZ628 treatment also inhibited the transcriptional activity and protein expression of FOXM1 and E2F4, mirroring the effects of SLC7A1 knockdown in meningioma. In brief, our study demonstrated the tumor-promoting function of SLC7A1 by regulating the transcription factors FOXM1 and E2F4 in meningioma and identified SLC7A1 as a potential therapeutic target. Meanwhile, AZ628 is a promising small molecule drug for high-grade meningioma.