Wu Zhiwei, Zhang Fan, Yang Kai, He Wenfei
Department of Organ Transplantation Center, Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China.
Department of Hepatobiliary Surgery, Haikou People's Hospital /Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, 570208, Hainan Province, People's Republic of China.
Sci Rep. 2025 Apr 10;15(1):12351. doi: 10.1038/s41598-025-96868-w.
Breast cancer is the leading cause of cancer-related death in women worldwide, and its developmental mechanisms involve complex factors. Recent studies have shown that ferroptosis is closely related to the occurrence and progression of breast cancer. However, the role of circular RNAs (circRNAs) in regulating ferroptosis in breast cancer remains unclear. In this study, we investigated the regulatory role of circSCD1 (hsa_circ_0019512) in breast cancer. We examined the expression of circSCD1 in breast cancer cell lines and explored its impact on cell viability and colony formation. We also evaluated the involvement of circSCD1 in ferroptosis by measuring the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and intracellular iron. In vivo xenograft experiments were performed to confirm the role of circSCD1 in promoting tumor growth and inhibiting ferroptosis.Furthermore, we investigated the mechanism by which circSCD1 regulates SCD1 protein stability through ubiquitination and identified the interaction between circSCD1 and the deubiquitinase OTUB1. Our results showed that circSCD1 was upregulated in breast cancer cell lines and promoted cell viability and colony formation. Knockdown of circSCD1 increased MDA and ROS levels, decreased GSH levels, and enhanced ferroptosis in breast cancer cells. In vivo, circSCD1 knockdown significantly reduced tumor size and weight, while its overexpression enhanced tumor growth. Mechanistically, circSCD1 interacted with OTUB1 to inhibit the ubiquitination and degradation of SCD1 protein, thereby stabilizing its expression. Rescue experiments demonstrated that SCD1 overexpression partially reversed the effects of circSCD1 knockdown on cell proliferation and ferroptosis. Our findings suggest that circSCD1 plays a crucial role in promoting breast cancer cell growth and inhibiting ferroptosis by regulating SCD1 protein stability. Targeting the circSCD1/OTUB1/SCD1 axis may provide a potential therapeutic strategy for breast cancer treatment.
乳腺癌是全球女性癌症相关死亡的主要原因，其发展机制涉及复杂因素。最近的研究表明，铁死亡与乳腺癌的发生和进展密切相关。然而，环状RNA（circRNA）在调节乳腺癌铁死亡中的作用仍不清楚。在本研究中，我们调查了circSCD1（hsa_circ_0019512）在乳腺癌中的调控作用。我们检测了circSCD1在乳腺癌细胞系中的表达，并探讨了其对细胞活力和集落形成的影响。我们还通过测量丙二醛（MDA）、谷胱甘肽（GSH）、活性氧（ROS）和细胞内铁水平来评估circSCD1在铁死亡中的作用。进行体内异种移植实验以证实circSCD1在促进肿瘤生长和抑制铁死亡中的作用。此外，我们研究了circSCD1通过泛素化调节SCD1蛋白稳定性的机制，并确定了circSCD1与去泛素化酶OTUB1之间的相互作用。我们的结果表明，circSCD1在乳腺癌细胞系中上调，促进细胞活力和集落形成。敲低circSCD1可增加MDA和ROS水平，降低GSH水平，并增强乳腺癌细胞的铁死亡。在体内，敲低circSCD1可显著减小肿瘤大小和重量，而其过表达则增强肿瘤生长。机制上，circSCD1与OTUB1相互作用以抑制SCD1蛋白的泛素化和降解，从而稳定其表达。拯救实验表明，SCD1过表达部分逆转了circSCD1敲低对细胞增殖和铁死亡的影响。我们的研究结果表明，circSCD1通过调节SCD1蛋白稳定性在促进乳腺癌细胞生长和抑制铁死亡中起关键作用。靶向circSCD1/OTUB1/SCD1轴可能为乳腺癌治疗提供一种潜在的治疗策略。
