# CDX2 confers ferroptosis resistance in stage II-III colon cancer via upregulation of NUPR1

## TL;DR

High CDX2 levels in colon cancer help cancer cells resist a type of cell death called ferroptosis by boosting NUPR1, which could lead to new treatment strategies.

## Contribution

The study reveals a new mechanism where CDX2 promotes ferroptosis resistance in colon cancer through NUPR1 upregulation.

## Key findings

- CDX2 increases NUPR1 to reduce iron accumulation and oxidative stress, preventing ferroptosis.
- Blocking the CDX2-NUPR1 axis enhances the effectiveness of ferroptosis-inducing drugs in colon cancer models.
- NUPR1 inhibition could be a potential treatment for CDX2-positive stage II-III colon cancer.

## Abstract

High CDX2 expression frequently indicates better survival in stage II-III colon cancer; nevertheless, it is linked to decreased systemic chemotherapy response rates. Ferroptosis, commonly recognized as an iron-dependent oxidative death, is increasingly believed as a disease-modifying mechanism. The purpose of this study is to determine the role of ferroptosis in CDX2-mediated colon cancer chemical resistance. Mechanistically, CDX2-mediated NUPR1 transcription prevents ferroptotic cell death by reducing iron accumulation and oxidative stress damage. Depletion of NUPR1 counteracted the effect of CDX2 overexpression in terms of ferroptosis resistance, whereas transfection-enforced re-expression of NUPR1 restores ferroptosis resistance in CDX2-deficient cells. Genetic or pharmacological blockage of CDX2-NUPR1 axis improved the potential of ferroptosis agonists to combat colon cancer in preclinical mouse models. Our study uncovered a novel molecular mechanism by which CDX2 imparts ferroptosis resistance to colon cancer. Blockage of NUPR1 might be as a potential therapeutic strategy for CDX2-positive stage II-III colon cancer.

The current study demonstrated a positive correlation between CDX2 expression and chemical resistance in colon cancer. Mechanistically, CDX2 directly transactivates NUPR1 and subsequent its target LCN2 to confer ferroptosis resistance by inhibiting iron-induced oxidative damage. Genetic or pharmacological blockage of CDX2-NUPR1 axis may strengthen the anticancer efficacy of adjuvant chemotherapy on stage II-III CDX2-positive colon cancer in vitro and in vivo. Our study uncovered a novel molecular mechanism by which CDX2 confers ferroptosis resistance in colon cancer. Blockage of NUPR1 might be as a potential therapeutic strategy for stage II-III CDX2-positive colon cancer.

The current study demonstrated a positive correlation between CDX2 expression and chemical resistance in colon cancer. Mechanistically, CDX2 directly transactivates NUPR1 and subsequent its target LCN2 to confer ferroptosis resistance by inhibiting iron-induced oxidative damage. Genetic or pharmacological blockage of CDX2-NUPR1 axis may strengthen the anticancer efficacy of adjuvant chemotherapy on stage II-III CDX2-positive colon cancer in vitro and in vivo. Our study uncovered a novel molecular mechanism by which CDX2 confers ferroptosis resistance in colon cancer. Blockage of NUPR1 might be as a potential therapeutic strategy for stage II-III CDX2-positive colon cancer.