Peroxiredoxin 1, pyroptosis, and the emerging frontier in colorectal cancer therapy

Abstract

Colorectal cancer (CRC) remains a major global health challenge, with high recurrence and mortality despite advances in surgery, chemotherapy, and immunotherapy. The study by He et al identifies a novel mechanism by which peroxiredoxin 1 (Prdx1) inhibits CRC progression through induction of pyroptosis, a pro-inflammatory form of programmed cell death. Traditionally viewed as an intracellular antioxidant that protects tumors from oxidative stress, Prdx1 assumes a paradoxical immunogenic role when released extracellularly as a damage-associated molecular pattern. Using patient samples, recombinant protein assays, and murine xenograft models, the authors demonstrate that Prdx1 activates the NOD-, LRR- and pyrin domain-containing protein 3 inflammasome/caspase-1/gasdermin D pathway, triggering membrane pore formation, tumor cell lysis, and release of interleukin-1β/interleukin-18. This cascade not only halts tumor proliferation, invasion, and migration but may also enhance anti-tumor immune surveillance. The study’s strengths include rigorous mechanistic validation, clinical cohort data, inhibitor-based causal proof, and in vivo confirmation. However, questions remain regarding the upstream receptor for Prdx1, heterogeneity across CRC subtypes, and the balance between therapeutic benefit and inflammatory toxicity. By establishing Prdx1-induced pyroptosis as a driver of tumor suppression, this work advances a promising paradigm in CRC therapy, linking cell death to immune activation and pointing toward future biomarker-driven, pyroptosis-based interventions.

Keywords: Colorectal cancer; Peroxiredoxin 1; Pyroptosis; Damage-associated molecular pattern; Immunogenic cell death

Core Tip: Peroxiredoxin 1, long regarded as an intracellular antioxidant that protect tumors from oxidative stress, assumes a paradoxical role in colorectal cancer therapy. He et al reveal that extracellular peroxiredoxin 1 acts as a damage-associated molecular pattern, activating the NOD-, LRR- and pyrin domain-containing protein 3 inflammasome/caspase-1/gasdermin D pathway to trigger pyroptosis. This lytic, pro-inflammatory death suppresses colorectal cancer proliferation, invasion, and migration while amplifying interleukin-1β/interleukin-18-mediated immune surveillance. Using patient cohorts, recombinant protein assays, and xenograft models, the study rigorously validates this mechanism.