# CILP2: From ECM Component to a Pleiotropic Modulator in Metabolic Dysfunction, Cancer, and Beyond

## TL;DR

CILP2 is a protein involved in various diseases like metabolic dysfunction and cancer, and it could serve as a potential biomarker and therapeutic target.

## Contribution

This review highlights CILP2's emerging role as an oncoprotein and its involvement in multiple diseases, offering new therapeutic insights.

## Key findings

- CILP2 is upregulated by metabolic stress and contributes to dyslipidemia, diabetes, and sarcopenia.
- CILP2 promotes tumor proliferation and metastasis through Akt/EMT signaling and immune infiltration.
- CILP2's dysregulation correlates with disease severity and poor prognosis, suggesting its potential as a biomarker.

## Abstract

Initially characterized as a component of the extracellular matrix (ECM) in cartilage, cartilage intermediate layer protein 2 (CILP2) is now recognized as a pleiotropic secretory protein with far-reaching roles in physiology and disease. This review synthesizes evidence establishing CILP2 as a key modulator at the nexus of metabolic dysfunction, cancer, and other pathologies. Genomic studies have firmly established the NCAN-CILP2 locus as a hotspot for genetic variants influencing dyslipidemia and cardiovascular risk. Functionally, CILP2 is upregulated by metabolic stress, including high glucose and oxidatively modified LDL (oxLDL), and actively contributes to pathologies such as dyslipidemia, diabetes, and sarcopenia by impairing glucose metabolism and mitochondrial function. Its role extends to fibrosis and neurodevelopment, promoting hypertrophic scar formation and neurogenesis through interactions with ATP citrate lyase (ACLY) and Wnt3a, respectively. More recently, CILP2 has emerged as an oncoprotein, overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma and colorectal cancer. It drives tumor proliferation and metastasis and correlates with tumor microenvironment remodeling through mechanisms involving Akt/EMT signaling and immune infiltration. The dysregulation of CILP2 in patient serum and its correlation with disease severity and poor prognosis highlight it as a promising biomarker and a compelling therapeutic target across a spectrum of human diseases.