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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\u2010endoplasmic 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\u2010dependent mechanisms: inhibiting apoptosis and facilitating post\u2010damage 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.<\/jats:p>","DOI":"10.1111\/bcpt.70257","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T08:10:51Z","timestamp":1781251851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting AVEN Liquid\u2010Liquid Phase Separation in Colorectal Cancer: Insights From a Raddeanin A\u2010Based Chemical Probe"],"prefix":"10.1111","volume":"139","author":[{"given":"Xichao","family":"Yu","sequence":"first","affiliation":[{"name":"School of Medicine Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine Nanjing University of Chinese Medicine  Nanjing 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