Redox Damage Tolerance Thresholds in KRAS-Driven Pancreatic Cancer Initiation

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers and is characterized by a high frequency of activating KRAS mutations, most commonly KRASG12D. Yet oncogenic KRAS alone is insufficient for malignant progression, indicating that additional cellular and environmental factors shape disease evolution. Obesity is a major modifiable risk factor for PDAC and creates a chronic metabolic environment marked by excess nutrient and lipid availability, inflammation, and altered redox homeostasis. In acinar cells, these conditions can increase metabolic and mitochondrial stress, promoting reactive oxygen species (ROS) generation and molecular and organellar damage. Cellular responses to such damage, however, do not necessarily lead to either complete recovery or cell death. Antioxidant defenses, autophagy, mitochondrial quality control, proteostasis, and DNA repair can contain or process damage, allowing cells to remain viable despite persistent or incompletely resolved injury. Thus, cellular fitness under chronic stress may depend not only on the amount of damage generated, but also on the capacity to tolerate damage while maintaining sufficient function. Here, we conceptualize the relationship between damage burden and cellular fitness as a dynamic redox damage tolerance threshold. Transient metabolic and redox stress may allow acinar cells undergoing acinar-to-ductal metaplasia (ADM) to return toward homeostasis, whereas sustained metabolic stress, as occurs in obesity, in the presence of oncogenic KRAS may enable ADM cells to remain functional despite residual damage. Such persistence may increase the opportunity for additional alterations and progression toward pancreatic intraepithelial neoplasia (PanIN). This framework places cellular damage tolerance, rather than damage generation alone, at the center of early PDAC development and highlights the mechanisms that determine this threshold as potential therapeutic vulnerabilities.