Chen Hongrui, Gao Wei, Huang Zening, Chang Shih-Jen, Qiu Yajing, Sun Bin, Lin Xiaoxi, Hua Chen
Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
Free Radic Biol Med. 2025 Nov;239:432-448. doi: 10.1016/j.freeradbiomed.2025.08.001. Epub 2025 Aug 5.
Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by excessive adipose tissue accumulation and infiltration, leading to severe functional and aesthetic impairments. Current surgical interventions face high recurrence rates and complications, necessitating exploration of molecular mechanisms driving FIL. N-methyladenosine (mA) RNA modification plays an essential role in modulating RNA stability and contribute to the regulation of adipogenesis. However, the detailed mechanism by which mA regulator regulates the pathogenesis of FIL remains unclear. We focused on FTO-mediated mA demethylation and evaluated FTO expression in FIL adipose tissues and adipose stem and progenitor cells (ASPCs) using Western blotting, qPCR, immunohistochemistry, and single-cell RNA sequencing. The regulatory mechanism of FTO on SLC7A11 was explored via MeRIP-seq, RIP-qPCR, and luciferase reporter assays. In vivo effects were evaluated using xenograft, NAC gavage, and AAV8-mediated SLC7A11 overexpression models. The mechanisms by which SLC7A11 influenced adipogenesis were investigated through ATAC-seq, ChIP-qPCR, and enzyme activity assays. FTO was upregulated in FIL tissues and ASPCs, correlating with reduced mA levels, enhanced adipogenesis, and disease severity. Mechanistically, FTO decreased mA modification of SLC7A11, impairing IGF2BP1-mediated stabilization and reducing SLC7A11 expression. This lowered cystine uptake and GSH/GSSG ratio, inhibiting SIRT6 activity and elevating H3K9ac at promoters of adipogenic genes (PPARG, CEBPA, FABP4), thereby enhancing chromatin openness and transcriptional activation. In vivo, SLC7A11 overexpression impaired adipogenic effects. Modulating GSH/GSSG ratios via NAC or BSO validated the redox-epigenetic axis in regulating adipogenesis. Our findings collectively demonstrate that FTO drives FIL progression by mA-dependent suppression of SLC7A11, disrupting redox balance and regulating SIRT6-H3K9ac-mediated epigenetic reprogramming to promote adipogenesis. Targeting the FTO/SLC7A11/GSH/SIRT6 axis offers a promising therapeutic strategy for FIL.
面部浸润性脂肪瘤病（FIL）是一种罕见的先天性疾病，其特征是脂肪组织过度积累和浸润，导致严重的功能和美学损害。目前的手术干预面临高复发率和并发症，因此有必要探索驱动FIL的分子机制。N-甲基腺苷（mA）RNA修饰在调节RNA稳定性中起重要作用，并有助于脂肪生成的调节。然而，mA调节剂调节FIL发病机制的详细机制仍不清楚。我们聚焦于FTO介导的mA去甲基化，并使用蛋白质免疫印迹法、定量聚合酶链反应、免疫组织化学和单细胞RNA测序评估了FIL脂肪组织以及脂肪干细胞和祖细胞（ASPCs）中FTO的表达。通过甲基化RNA免疫沉淀测序、RNA免疫沉淀定量聚合酶链反应和荧光素酶报告基因检测，探索了FTO对溶质载体家族7成员11（SLC7A11）的调控机制。使用异种移植、N-乙酰半胱氨酸灌胃和腺相关病毒8介导的SLC7A11过表达模型评估体内效应。通过染色质转座酶可及性测序、染色质免疫沉淀定量聚合酶链反应和酶活性检测，研究了SLC7A11影响脂肪生成的机制。FTO在FIL组织和ASPCs中上调，与mA水平降低、脂肪生成增强和疾病严重程度相关。从机制上讲，FTO降低了SLC7A11的mA修饰，损害了胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）介导的稳定性并降低了SLC7A11的表达。这降低了胱氨酸摄取和谷胱甘肽/氧化型谷胱甘肽比值，抑制了沉默调节蛋白6（SIRT6）的活性，并提高了脂肪生成基因（过氧化物酶体增殖物激活受体γ、CCAAT增强子结合蛋白α、脂肪酸结合蛋白4）启动子处的组蛋白H3赖氨酸9乙酰化水平，从而增强了染色质开放性和转录激活。在体内，SLC7A11过表达损害了脂肪生成作用。通过N-乙酰半胱氨酸或丁硫氨酸亚砜胺调节谷胱甘肽/氧化型谷胱甘肽比值，验证了氧化还原-表观遗传轴在调节脂肪生成中的作用。我们的研究结果共同表明，FTO通过mA依赖性抑制SLC7A11驱动FIL进展，破坏氧化还原平衡并调节SIRT6-组蛋白H3赖氨酸9乙酰化介导的表观遗传重编程以促进脂肪生成。靶向FTO/SLC7A11/谷胱甘肽/SIRT6轴为FIL提供了一种有前景的治疗策略。
