Lee Woonghee, Song Gwonhwa, Bae Hyocheol
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
Bioorg Chem. 2025 May 29;163:108636. doi: 10.1016/j.bioorg.2025.108636.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options and poor patient survival. Despite the use of combination chemotherapy regimens, including FOLFIRINOX and gemcitabine-based therapies, the majority of patients experience relapse, underscoring the urgent need for novel therapeutic strategies. Gracillin, a natural triterpenoidal saponin, has demonstrated anticancer potential in various malignancies; however, its effects on PDAC and underlying molecular mechanisms remain unexplored. In this study, we provide the first comprehensive investigation of the anticancer properties of gracillin in PDAC. Our findings demonstrate that gracillin effectively inhibits PDAC cell viability, induces mitochondria-mediated apoptosis, and promotes oxidative damage by disrupting intracellular redox homeostasis. Mechanistically, gracillin exerts its effects by inhibiting the NRF2/HO-1 antioxidant axis, leading to excessive reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Molecular docking and molecular dynamics simulations further revealed a strong binding affinity between gracillin and NRF2, suggesting that gracillin may act as a direct NRF2 inhibitor. To further validate that anticancer effects of gracillin are mediated through NRF2 inhibition, we also assessed the impact of combining gracillin treatment with siRNA-mediated NRF2 silencing. Additionally, we found that gracillin enhances the cytotoxicity of gemcitabine, exhibiting a synergistic effect in PDAC cells. Finally, in vivo xenograft studies confirmed the tumor-suppressive effects of gracillin, further validating its potential as an effective therapeutic agent for PDAC. Overall, our study elucidates the potential of gracillin as a promising anticancer agent targeting the NRF2/HO-1 axis to disrupt redox homeostasis in PDAC. These findings provide new insights into the development of NRF2-targeted therapies for overcoming chemoresistance in PDAC.
胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，治疗选择有限，患者生存率低。尽管使用了包括FOLFIRINOX和基于吉西他滨的联合化疗方案，但大多数患者仍会复发，这凸显了对新型治疗策略的迫切需求。Gracillin是一种天然三萜皂苷，已在多种恶性肿瘤中显示出抗癌潜力；然而，其对PDAC的作用及潜在分子机制仍未得到探索。在本研究中，我们首次全面研究了Gracillin在PDAC中的抗癌特性。我们的研究结果表明，Gracillin可有效抑制PDAC细胞活力，诱导线粒体介导的凋亡，并通过破坏细胞内氧化还原稳态促进氧化损伤。机制上，Gracillin通过抑制NRF2/HO-1抗氧化轴发挥作用，导致活性氧（ROS）过度积累和线粒体功能障碍。分子对接和分子动力学模拟进一步揭示了Gracillin与NRF2之间有很强的结合亲和力，表明Gracillin可能作为直接的NRF2抑制剂。为进一步验证Gracillin的抗癌作用是通过抑制NRF2介导的，我们还评估了Gracillin治疗与siRNA介导的NRF2沉默联合使用的影响。此外，我们发现Gracillin增强了吉西他滨的细胞毒性，在PDAC细胞中表现出协同作用。最后，体内异种移植研究证实了Gracillin的肿瘤抑制作用，进一步验证了其作为PDAC有效治疗剂的潜力。总体而言，我们的研究阐明了Gracillin作为一种有前景的抗癌剂，靶向NRF2/HO-1轴破坏PDAC氧化还原稳态的潜力。这些发现为开发针对NRF2的疗法以克服PDAC化疗耐药性提供了新的见解。
