P62 in colorectal cancer: from inflammation suppression to cancer promotion

The autophagy adaptor and scaffold protein p62 plays a critical role in colorectal cancer (CRC) progression. As a malignancy driven by chronic inflammation, CRC arises from the combined effects of oncogenic signaling activation, genetic mutations, and epithelial barrier disruption. During early stages of inflammation, p62 exerts tumor-suppressive functions by clearing inflammasomes, activating NRF2, and downregulating inflammatory cytokines. However, sustained inflammation leads to p62 accumulation, which reinforces the activation of NRF2, NF-κB, and mTORC1 pathways through positive feedback loops, thereby driving tumorigenesis. Excessive p62 also impairs DNA double-strand break repair, facilitating oncogenic mutations. These observations indicate that enhancing autophagic clearance of p62 could represent a promising therapeutic strategy to prevent inflammation-associated CRC.