# Machine Learning-Driven Multi-Omics Analysis Identifies CHP2 as a Key PANoptosis-Related Dual-Function Biomarker in Colorectal Cancer

## TL;DR

CHP2 is a key tumor suppressor in colorectal cancer that helps predict prognosis and treatment response by triggering cell death and identifying drug-resistant patients.

## Contribution

Identifies CHP2 as a dual-function biomarker for prognosis and targeted therapy in drug-resistant colorectal cancer.

## Key findings

- CHP2 inhibits CRC cell proliferation and invasion by inducing PANoptosis.
- Low CHP2 expression correlates with poor prognosis and an immunosuppressive tumor environment.
- CHP2 deficiency identifies patients resistant to chemotherapy but responsive to targeted inhibitors like Ribociclib or Lapatinib.

## Abstract

What are the main findings?
CHP2 was identified as a key tumor suppressor in colorectal cancer that inhibits cell proliferation and invasion by triggering PANoptosis (necroptosis, pyroptosis, and apoptosis).Low CHP2 expression characterizes a high-risk patient group associated with an immunosuppressive “cold” tumor microenvironment and poor clinical prognosis.

CHP2 was identified as a key tumor suppressor in colorectal cancer that inhibits cell proliferation and invasion by triggering PANoptosis (necroptosis, pyroptosis, and apoptosis).

Low CHP2 expression characterizes a high-risk patient group associated with an immunosuppressive “cold” tumor microenvironment and poor clinical prognosis.

What are the implications of the main findings?
CHP2 serves as a dual-function biomarker, providing a molecular basis for both prognostic risk stratification and the prediction of therapeutic response.CHP2 deficiency identifies patients resistant to standard chemotherapy who may selectively benefit from targeted inhibitors such as Ribociclib or Lapatinib.

CHP2 serves as a dual-function biomarker, providing a molecular basis for both prognostic risk stratification and the prediction of therapeutic response.

CHP2 deficiency identifies patients resistant to standard chemotherapy who may selectively benefit from targeted inhibitors such as Ribociclib or Lapatinib.

The heterogeneity of colorectal cancer (CRC) represents a great challenge in therapy. We integrated multiomics and machine learning, interpreted by SHAP models to provide a clinical rationale, to identify Calcineurin B Homologous Protein 2 (CHP2) as a core candidate, which was further validated via in vitro and zebrafish models. The expression of CHP2 are decreased in CRC, which is associated with a poor prognosis and an immune suppressed “cold” TIME. Functionally, CHP2 overexpression inhibits cell growth and invasion by inducing PANoptosis. Clinically, specific CHP2 expression profiles discriminate patients at high risk that are resistant to standard chemotherapy (e.g., 5-FU) but sensitive to targeted inhibitors. CHP2 is a powerful dual-function biomarker—prognostic for survival and predictive for the response to therapy—that could lead to a personalized approach in treating drug-resistant CRC.