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<p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and treatment-resistant malignancy with a poor prognosis. Among the multifactorial mechanisms implicated in the progression of PDAC, oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidant defenses, has emerged as a crucial regulator of tumor behavior. While ROS can promote tumorigenesis via genomic instability, oncogenic signaling, and immune evasion, it also exhibits tumor-suppressive potential by inducing apoptosis and disrupting cancer cell metabolism. This dual role of ROS in PDAC is tightly influenced by the tumor mutational landscape, particularly KRAS gene mutations, metabolic reprogramming, and the tumor microenvironment. In PDAC, the generation of ROS promotes chemoresistance, activates hypoxia-inducible factor-1α, and facilitates desmoplastic stromal remodeling via pancreatic stellate cells and cancer-associated fibroblasts. Conversely, the therapeutic increase of ROS beyond tolerable levels induces cancer cell death through apoptosis and autophagy. This review comprehensively summarizes the dual role of ROS in PDAC, with particular emphasis on the molecular mechanisms underlying redox regulation. In addition, ROS-targeting therapeutic agents are categorized into clinically approved drugs, investigational agents, and natural compounds, and their relevance in redox biology is discussed. Finally, emerging therapeutic strategies that leverage redox vulnerabilities are outlined, and future research directions are proposed for the development of redox-modulating PDAC therapies.</p>

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Oxidative stress and pancreatic cancer: a dual role in tumorigenesis and drug toxicity

  • 期刊论文

  • 发表日期：

    2025年7月13日

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  • Khem Raj Limbu,
  • Rashmi Bhandari Chhetri,
  • Yoon Sin Oh,
  • Min-Ho Oak,
  • Dong Jae Beak,
  • Eun-Young Park

摘要

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and treatment-resistant malignancy with a poor prognosis. Among the multifactorial mechanisms implicated in the progression of PDAC, oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidant defenses, has emerged as a crucial regulator of tumor behavior. While ROS can promote tumorigenesis via genomic instability, oncogenic signaling, and immune evasion, it also exhibits tumor-suppressive potential by inducing apoptosis and disrupting cancer cell metabolism. This dual role of ROS in PDAC is tightly influenced by the tumor mutational landscape, particularly KRAS gene mutations, metabolic reprogramming, and the tumor microenvironment. In PDAC, the generation of ROS promotes chemoresistance, activates hypoxia-inducible factor-1α, and facilitates desmoplastic stromal remodeling via pancreatic stellate cells and cancer-associated fibroblasts. Conversely, the therapeutic increase of ROS beyond tolerable levels induces cancer cell death through apoptosis and autophagy. This review comprehensively summarizes the dual role of ROS in PDAC, with particular emphasis on the molecular mechanisms underlying redox regulation. In addition, ROS-targeting therapeutic agents are categorized into clinically approved drugs, investigational agents, and natural compounds, and their relevance in redox biology is discussed. Finally, emerging therapeutic strategies that leverage redox vulnerabilities are outlined, and future research directions are proposed for the development of redox-modulating PDAC therapies.