Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang, 310022, China.
Adv Sci (Weinh). 2024 May;11(18):e2307899. doi: 10.1002/advs.202307899. Epub 2024 Mar 9.
Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin-specific protease 7 (USP7) plays pivotal roles in GC development, immune response, and chemo-resistance, making it a promising target. Various USP7 inhibitors have shown selectivity and efficacy in preclinical studies. However, the mechanistic role of USP7 has not been fully elucidated, and currently, no USP7 inhibitors have been approved for clinical use. In this study, DHPO is identified as a potent USP7 inhibitor for GC treatment through in silico screening. DHPO demonstrates significant anti-tumor activity in vitro, inhibiting cell viability and clonogenic ability, and preventing tumor migration and invasion. In vivo studies using orthotopic gastric tumor mouse models validate DHPO's efficacy in suppressing tumor growth and metastasis without significant toxicity. Mechanistically, DHPO inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, and iron overload. Further investigations unveil USP7's regulation of Stearoyl-CoA Desaturase (SCD) through deubiquitination, linking USP7 inhibition to SCD degradation and ferroptosis induction. Overall, this study identifies USP7 as a key player in ferroptosis of GC, elucidates DHPO's inhibitory mechanisms, and highlights its potential for GC treatment by inducing ferroptosis through SCD regulation.
胃癌（GC）是一个严峻的全球性健康挑战，传统疗法的疗效受到限制。泛素特异性蛋白酶 7（USP7）在 GC 发展、免疫反应和化疗耐药性中起着关键作用，使其成为一个有前途的靶点。各种 USP7 抑制剂在临床前研究中表现出选择性和疗效。然而，USP7 的作用机制尚未完全阐明，目前尚无 USP7 抑制剂被批准用于临床应用。在这项研究中，通过计算机筛选，确定 DHPO 是一种有效的 GC 治疗 USP7 抑制剂。DHPO 在体外具有显著的抗肿瘤活性，抑制细胞活力和克隆形成能力，并防止肿瘤迁移和侵袭。使用原位胃肿瘤小鼠模型的体内研究验证了 DHPO 在抑制肿瘤生长和转移方面的疗效，而没有明显的毒性。在机制上，DHPO 抑制通过线粒体改变、脂质活性氧（ROS）、丙二醛（MDA）积累和铁过载触发铁死亡。进一步的研究揭示了 USP7 通过去泛素化调节硬脂酰辅酶 A 去饱和酶（SCD），将 USP7 抑制与 SCD 降解和铁死亡诱导联系起来。总之，这项研究确定了 USP7 是 GC 中铁死亡的关键调节因子，阐明了 DHPO 的抑制机制，并通过 SCD 调节诱导铁死亡，强调了其在 GC 治疗中的潜力。
