Targeting AVEN Liquid-Liquid Phase Separation in Colorectal Cancer: Insights From a Raddeanin A-Based Chemical Probe

Area of Science:

• Biochemistry
• Cell Biology
• Cancer Research

Background:

• Mitochondrial dysfunction and dysregulated liquid-liquid phase separation (LLPS) are key in colorectal cancer (CRC) pathogenesis.
• The precise mechanisms and therapeutic targets for these processes remain largely unknown.

Purpose of the Study:

• To investigate the role of LLPS in mitochondrial dysfunction in CRC.
• To identify and validate novel therapeutic targets for CRC.

Main Methods:

• Multi-omics analysis and biophysical assays were employed.
• Raddeanin A was used as a probe to identify potential targets.
• In vitro and in vivo models, including mouse models and clinical cohorts, were utilized.

Main Results:

• Apoptosis and caspase activation inhibitor (AVEN) was identified as a significantly upregulated protein in CRC tissues, localized near mitochondria-endoplasmic reticulum contact sites (MERCS).
• AVEN undergoes LLPS via its intrinsically disordered regions (IDRs), orchestrating mitochondrial homeostasis by inhibiting apoptosis and facilitating mitochondrial transfer.
• Sumatriptan (SUM) was identified as a potent inhibitor of AVEN IDRs, demonstrating significant therapeutic efficacy.

Conclusions:

• AVEN plays a critical role in regulating mitochondrial homeostasis through LLPS in CRC.
• Targeting AVEN via its IDRs represents a promising therapeutic strategy for colorectal cancer.