Targeting AVEN liquid-liquid phase separation in colorectal cancer with a Raddeanin A-based probe

Abstract

Mitochondrial dysfunction is a pivotal pathogenic mechanism in colorectal cancer (CRC), which is further exacerbated by dysregulated liquid-liquid phase separation (LLPS). However, the mechanisms underlying mitochondrial dysfunction and LLPS, as well as their therapeutic targeting, remain unclear. Using Raddeanin A as a probe and through multiomics analysis, we identified apoptosis and caspase activation inhibitor (AVEN) as a potential therapeutic target. AVEN was significantly upregulated in CRC tissues and localized near mitochondria-endoplasmic reticulum contact sites (MERCS). Biophysical assays confirmed that AVEN undergoes LLPS via its intrinsically disordered regions (IDRs). Critically, we found that AVEN IDRs orchestrate mitochondrial homeostasis through dual LLPS-dependent mechanisms: inhibiting apoptosis and facilitating post-damage mitochondrial transfer. Furthermore, we identified sumatriptan (SUM) as a potent inhibitor of AVEN IDRs, which demonstrated promising therapeutic efficacy in mouse models and clinical cohorts. Our study highlights the critical role of AVEN in regulating mitochondrial homeostasis via LLPS and suggests that targeting AVEN represents a promising therapeutic strategy for CRC.