胰腺导管腺癌 (PDAC) 的特点是基质显着硬化和葡萄糖代谢重新编程，特别是 Warburg 效应。然而，这些特征之间复杂的相互作用及其对肿瘤进展的影响仍未得到充分探索。在这里，我们整合了临床、细胞和生物信息学方法来探索 PDAC 中基质刚度和 Warburg 效应之间的联系，并将 CLIC1 确定为关键介质。通过 Wnt/β-catenin/TCF4 信号传导由基质硬度诱导的 CLIC1 表达升高，意味着 PDAC 的预后结果较差。从功能上讲，CLIC1 作为糖酵解代谢的催化剂，促进肿瘤增殖。从机制上讲，CLIC1 通过活性氧 (ROS) 抑制羟基化，从而增强 HIF1α 的稳定性。总的来说，PDAC 细胞以基质硬度响应方式提高 CLIC1 水平，增强 Warburg 效应，通过 ROS/HIF1α 信号传导驱动肿瘤生长。我们的见解强调了同时解决基质特性和代谢重连的靶向治疗的机会，其中 CLIC1 正在成为一个有前途的干预点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/β-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.