Rewiring redox defense: Nrf2-driven antioxidant signaling as a gateway to programmed cell death activation in colorectal cancer

Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant and phase II detoxification genes, plays a dual role in colorectal cancer (CRC) progression by maintaining redox homeostasis while paradoxically fostering chemoresistance. Programmed cell death (PCD) pathways, including apoptosis, ferroptosis, and autophagy, play a crucial role in the pathogenesis and therapeutic responsiveness of CRC, largely through mechanisms mediated by reactive oxygen species (ROS). Emerging evidence highlights that pharmacological agents or natural compounds targeting PCD trigger ROS accumulation, selectively impairing the survival of CRC cells due to their increased dependency on ROS. Although Nrf2's dual roles have been extensively characterized, the specific interactions between Nrf2-mediated redox regulation and PCD modulation are not yet fully understood, thereby constraining the advancement of redox-based therapeutic strategies. This review synthesizes recent advances in Nrf2 activity modulation within PCD-centric CRC treatment paradigms, emphasizing its context-dependent roles in ROS management. Furthermore, we propose rational strategies to harness Nrf2 inhibitors or activators, either as monotherapies or in combination with conventional regimens, to overcome chemoresistance and amplify therapeutic efficacy. By bridging mechanistic insights with therapeutic potential, this work underscores Nrf2 as a pivotal node for redefining redox-targeted CRC interventions. This narrative review systematically summarizes literature on Nrf2, ROS, and PCD pathways (apoptosis, ferroptosis, autophagy) in CRC. Literature searches were conducted in PubMed and Web of Science using the following keywords: (“Nrf2” OR “NFE2L2”) AND (“colorectal cancer” OR “CRC”) AND (“apoptosis” OR “ferroptosis” OR “autophagy” OR “programmed cell death” OR “ROS” OR “oxidative stress”). Searches were limited to English-language articles published between 2010 and 2024, with priority given to recent (2018–2024) in vivo and in vitro , clinical, and mechanistic studies. Reviews and studies focusing on other cancers were excluded. Additional articles were identified via reference lists of key reviews and original studies. Data were synthesized to highlight mechanistic links between Nrf2, ROS, and PCD, as well as translational therapeutic strategies.