Zhang Xue, Zhu Biwen, Yan Jiashuai, Chen Xi, Wu Di, Wang Zhen, Guan Xiaoqi, Huang Yan, Zhao Yahong, Yang Yumin, Guo Yibing
Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, PR China.
Key Laboratory of Neuro-regeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuro-regeneration, Nantong University, Nantong 226001, PR China.
Regen Biomater. 2025 Jun 16;12:rbaf056. doi: 10.1093/rb/rbaf056. eCollection 2025.
PDAC cells perceive and respond to mechanical stimuli in their extracellular microenvironments (ECMs), playing a crucial role in chemoresistance, while the underlying mechanisms are not fully understood. The progression of various solid tumors is accompanied by metabolic reprogramming. RNA-seq and untargeted metabolomics analysis indicated that stiff substrate may regulate lipid metabolism. The expression of lipogenesis-related genes, including fatty acid synthase (FASN), ATP citrate lyase (ACLY) and acetyl-CoA carboxylase (ACC) was elevated, also the sum of lipid droplets and the triglyceride content. Herein, whether lipid metabolism is involved in matrix stiffness-mediated PDAC chemoresistance and the in-depth mechanism were further explored. Rescue with C75 (FASN inhibitor) validated that fatty acid synthesis participated in matrix stiffness-regulated chemoresistance. Simultaneously, the SCD1 expression was reinforced, consistent with PDAC tissues. The concurrent restraint SCD1 (with inhibitor CAY10566 or shSCD1) and addition of oleic acid confirmed that SCD1 is involved in matrix stiffness-mediated chemoresistance through fatty acid synthesis. In addition, Piezo1 regulated SCD1 expression through the augmentation of Ca influx, and the PI3K/Akt pathway participated in this process. Taken together, our research sheds light on lipid metabolism exerts an essential role during matrix stiffness-mediated chemoresistance through Piezo1-elicited elevation of SCD1. Our findings delivered a supplement PDAC chemoresistance mechanism mediated by matrix stiffness from the perspective of lipid metabolic reprogramming, and provided a novel strategy for improving clinical therapies.
胰腺导管腺癌（PDAC）细胞能够感知并响应其细胞外微环境（ECM）中的机械刺激，在化疗耐药中发挥关键作用，但其潜在机制尚未完全明确。各种实体瘤的进展都伴随着代谢重编程。RNA测序和非靶向代谢组学分析表明，坚硬的底物可能调节脂质代谢。包括脂肪酸合酶（FASN）、ATP柠檬酸裂解酶（ACLY）和乙酰辅酶A羧化酶（ACC）在内的脂肪生成相关基因的表达升高，脂质滴的总和以及甘油三酯含量也升高。在此，进一步探讨脂质代谢是否参与基质硬度介导的PDAC化疗耐药及其深入机制。用C75（FASN抑制剂）进行挽救实验证实脂肪酸合成参与了基质硬度调节的化疗耐药。同时，硬脂酰辅酶A去饱和酶1（SCD1）的表达增强，这与PDAC组织一致。同时抑制SCD1（使用抑制剂CAY10566或shSCD）并添加油酸证实，SCD1通过脂肪酸合成参与基质硬度介导的化疗耐药。此外，Piezo1通过增加钙离子内流调节SCD1的表达，并且PI3K/Akt信号通路参与了这一过程。综上所述，我们的研究揭示了脂质代谢在基质硬度介导的化疗耐药过程中通过Piezo1引发的SCD1升高发挥重要作用。我们的研究结果从脂质代谢重编程的角度补充了基质硬度介导的PDAC化疗耐药机制，并为改善临床治疗提供了新策略。
