胃癌仍然是最常见的致命疾病之一，缺乏有效的靶向治疗。本研究证实，信号转导和转录激活因子3（STAT3）在胃癌中高度表达且与不良预后相关。我们进一步发现了一种新的天然产物STAT3抑制剂，称为XYA-2，它与STAT3的SH2结构域特异性相互作用（Kd= 3.29 μM），并抑制IL-6诱导的STAT3在Tyr705的磷酸化和核转运。XYA-2抑制了七种人胃癌细胞株的生存率，72小时IC50值分别为0.5至0.7 μΜ。 1μΜ的XYA-2抑制了MGC803（分别为72.6％和67.6％）和MKN28（分别为78.5％和96.6％）细胞的集落形成和迁移能力。在体内研究中，腹腔注射XYA-2（每日10mg/kg，每周7天）显著抑制了MKN28衍生的裸鼠异种移植模型和MGC803衍生的正位移植模型中59.8％和88.8％的肿瘤生长。在患者来源的异种移植（PDX）小鼠模型中也获得了类似的结果。此外，XYA-2治疗延长了携带PDX肿瘤的小鼠的生存时间。基于转录组和蛋白质组的分析，分子机制研究表明，XYA-2可能通过协同抑制MYC和SLC39A10的表达，在体内外发挥其抗癌活性。这些发现表明，XYA-2可能是治疗胃癌的有效STAT3抑制剂，并且对于STAT3激活的癌症，双重抑制MYC和SLC39A10可能是一种有效的治疗策略。版权所有©2023 The Authors。由Elsevier Ltd.出版。保留所有权利。

Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 (Kd= 3.29 μM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC50 values ranging from 0.5 to 0.7 μΜ. XYA-2 at 1 μΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10 mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.