Chen Yichi, Lin Xin, Qiu Jiayue, Sun Yucao, Wu Bolin, Shang Haitao, Deng Liwen, Wang Xi, Li Nanxing, Huang Chen, Zhang Tianhong, Wu Zhiguang, Hou Gang, Yan Xiaohui, Wang Shoufeng, Cheng Wen
Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin 150081, China.
Dr. Nesher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China.
Ultrason Sonochem. 2025 Apr 23;118:107368. doi: 10.1016/j.ultsonch.2025.107368.
Disulfidptosis, a newly identified regulated cell death, is linked to tumor progression, particularly in cancers with elevated SLC7A11 expression. This study investigates SLC7A11 expression in liver hepatocellular carcinoma (LIHC) and evaluates the therapeutic potential of ICG@C3F8-KL nanobubbles (NBs) combined with sonodynamic therapy (SDT) for inducing disulfidptosis. Bioinformatics analysis of TCGA datasets revealed upregulation of SLC7A11 in LIHC tissues. The synthesized ICG@C3F8-KL NBs exhibited a mean diameter of 156.46 nm and stable properties, with high encapsulation efficiencies of 51.32 % ± 0.7 % for KL and 80.15 % ± 0.21 % for ICG. In vitro, ICG@C3F8-KL NBs, under ultrasound, generated reactive oxygen species (ROS), enhancing cytotoxicity in HepG2 cells with an IC50 lower than KL alone. These NBs also inhibited cell migration and colony formation, suggesting disulfidptosis induction via altered glucose uptake and NADP+/NADPH ratio, as well as F-actin contraction. In vivo, ICG@C3F8-KL NBs accumulated in tumor tissues and suppressed growth without significant toxicity. Unsupervised clustering of disulfidptosis-related genes in TCGA LIHC cohort identified subtypes with distinct prognoses, and a predictive model based on five key genes was developed. In conclusion, ICG@C3F8-KL NBs, combined with ultrasound, effectively induce disulfidptosis, offering a promising strategy for LIHC treatment, with the potential for personalized therapy informed by disulfide-associated gene signatures.
二硫化物诱导的细胞死亡是一种新发现的受调控的细胞死亡方式，与肿瘤进展相关，尤其是在SLC7A11表达升高的癌症中。本研究调查了SLC7A11在肝细胞癌（LIHC）中的表达，并评估了ICG@C3F8-KL纳米气泡（NBs）联合声动力疗法（SDT）诱导二硫化物诱导的细胞死亡的治疗潜力。对TCGA数据集的生物信息学分析显示，LIHC组织中SLC7A11上调。合成的ICG@C3F8-KL NBs平均直径为156.46 nm，性质稳定，KL的包封率为51.32%±0.7%，ICG的包封率为80.15%±0.21%。在体外，ICG@C3F8-KL NBs在超声作用下产生活性氧（ROS），增强了对HepG2细胞的细胞毒性，其IC50低于单独使用KL时。这些NBs还抑制细胞迁移和集落形成，提示通过改变葡萄糖摄取、NADP+/NADPH比值以及F-肌动蛋白收缩诱导二硫化物诱导的细胞死亡。在体内，ICG@C3F8-KL NBs在肿瘤组织中蓄积并抑制肿瘤生长，且无明显毒性。对TCGA LIHC队列中二硫化物诱导的细胞死亡相关基因进行无监督聚类，确定了具有不同预后的亚型，并建立了基于五个关键基因的预测模型。总之，ICG@C3F8-KL NBs联合超声能有效诱导二硫化物诱导的细胞死亡，为LIHC治疗提供了一种有前景的策略，并有可能通过二硫键相关基因特征实现个性化治疗。
