CHTOP regulates the NRF2/HO-1 axis to modulate chemoresistance in colorectal cancer.

Chemotherapy resistance remains a significant challenge in colorectal cancer (CRC) treatment, with disrupted redox balance playing a central role. Here we identify CHTOP as a key regulator of oxidative stress and chemoresistance in CRC. Mechanistically, CHTOP promotes NRF2 transcriptional activity by recruiting the SENP3-containing 5FMC complex to deSUMOylate NRF2, thereby sustaining HO-1 expression and redox balance. Notably, CHTOP expression itself is tightly controlled by a feedback mechanism. The p52 isoform of PSIP1 inhibits CHTOP expression by interfering with HNRNPH1-mediated splicing, leading to CHTOP degradation via nonsense-mediated decay (NMD). Conversely, elevated oxidative stress stabilizes SENP3, which promotes deSUMOylation and degradation of p52, thereby relieving p52-mediated suppression of CHTOP expression. This establishes an oxidative stress-SENP3-p52-CHTOP feedback loop that fine-tunes CHTOP levels. In 5-FU-resistant CRC cells, CHTOP downregulation shifts cells into an elevated oxidative stress state, which correlates with reduced 5-FU sensitivity. Notably, either restoring CHTOP expression or further depleting CHTOP disrupts this redox balance and resensitizes resistant cells to 5-FU. These findings suggest that modulating CHTOP expression may offer a therapeutic strategy to overcome chemoresistance in CRC through redox regulation.