Gao Anbo, Zou Juan, Zeng Tian, Qin Mei, Tang Xing, Yi Ting, Song Guangming, Zhong Jie, Zeng Yuhuan, Zhou Wenchao, Gao Qin, Zhang Qunfeng, Zhang Juan, Li Yukun
Clinical Research Institute, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, China.
Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Cell Death Dis. 2025 Apr 17;16(1):308. doi: 10.1038/s41419-025-07571-7.
Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The impact of ESM1 on lipid metabolism was investigated through the regulation of ESM1 expression. Differential genes regulated by ESM1 were screened by mRNA sequencing. The role of autophagy in ESM1 regulation on lipid metabolism was explored using autophagy inhibitor chloroquine (CQ). Co-IP, dual-luciferase reporter assay, actinomycin D treatment assay, and others were used to analyze the mechanism of ESM1 regulation on lipid metabolism. The xenograft mouse model was constructed to explore the impact of ESM1 regulation on OC development. The regulatory mechanism of ESM1 in OC patient samples was verified by using microarray analysis and the Log-rank (Mantel-Cox) test. After ESM1 silencing, cholesterol synthesis decreased and lipolysis increased. mRNA sequencing revealed that ESM1 regulation on lipid metabolism was related to Beclin 1 (BECN1). In vitro experiments, ESM1 inhibited lipolysis by suppressing BECN1-mediated autophagy. BECN1 expression was regulated by the transcription factor Kruppel-like factor 10 (KLF10). The competitive binding between BECN1 and HSPA5 promoted the ubiquitination degradation of HMGCR, thereby inhibiting cholesterol production. The intervention experiment with exogenous cholesterol showed a positive correlation between m6A reader IGF2BP3 expression and cholesterol content. Mechanistically, IGF2BP3 regulated the stability of ESM1 mRNA. In vivo experiments, ESM1 modified by m6A methylation promoted cholesterol synthesis and inhibited lipolysis. High expression of ESM1 predicted poor prognosis in OC patients. ESM1 regulated lipid metabolism through IGF2BP3/ESM1/KLF10/BECN1 positive feedback, which was a promising target for OC treatment.
卵巢癌（OC）通常在晚期被检测到，并且在手术或化疗后具有较高的复发率。因此，开发新的OC治疗策略至关重要。本研究旨在探究内皮细胞特异性分子1（ESM1）在OC中的作用。通过调节ESM1表达来研究ESM1对脂质代谢的影响。通过mRNA测序筛选受ESM1调控的差异基因。使用自噬抑制剂氯喹（CQ）探索自噬在ESM1对脂质代谢调控中的作用。采用免疫共沉淀、双荧光素酶报告基因检测、放线菌素D处理检测等方法分析ESM1对脂质代谢的调控机制。构建异种移植小鼠模型以探究ESM1调控对OC发展的影响。通过微阵列分析和对数秩（Mantel-Cox）检验验证ESM1在OC患者样本中的调控机制。ESM1沉默后，胆固醇合成减少，脂解增加。mRNA测序显示ESM1对脂质代谢的调控与Beclin 1（BECN1）有关。在体外实验中，ESM1通过抑制BECN1介导的自噬来抑制脂解。BECN1表达受转录因子Kruppel样因子10（KLF10）调控。BECN1与HSPA5之间的竞争性结合促进了HMGCR的泛素化降解，从而抑制胆固醇生成。外源性胆固醇干预实验表明m6A阅读器IGF2BP3表达与胆固醇含量呈正相关。机制上，IGF2BP3调节ESM1 mRNA的稳定性。在体内实验中，经m6A甲基化修饰的ESM1促进胆固醇合成并抑制脂解。ESM1高表达预示OC患者预后不良。ESM1通过IGF2BP3/ESM1/KLF10/BECN1正反馈调节脂质代谢，这是OC治疗的一个有前景的靶点。
