Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China.
Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China.
Nat Commun. 2024 May 20;15(1):4296. doi: 10.1038/s41467-024-48307-z.
Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.
治疗抵抗是晚期胃癌（GC）治疗的一个瓶颈。铁死亡是一种依赖铁的非凋亡性细胞死亡形式，与抗癌治疗效果相关。需要进一步的研究来阐明其潜在机制。构建铁死亡抗性 GC 细胞系。鉴定铁死亡抗性和亲本细胞系之间失调的 mRNA。在相关的生物学和分子分析中操纵 GC 细胞系中 SOX13/SCAF1 的表达。进行分子对接和计算筛选，以筛选 SOX13 的潜在抑制剂。我们表明，SOX13 通过直接反式激活 SCAF1 来促进电子传递链（ETC）复合物的蛋白质重塑。这导致超复合物（SCs）组装、线粒体呼吸、线粒体能量和化学及免疫耐药性增加。扎那米韦通过直接靶向 SOX13 并促进 TRIM25 介导的 SOX13 泛素化和降解，逆转铁死亡抗性表型。在这里，我们表明 SOX13/SCAF1 在铁死亡抗性中很重要，用扎那米韦靶向 SOX13 具有治疗潜力。
