Here we report that CRYAB phosphorylation serves as a key driver of colorectal cancer liver metastatic progression, and establish usnic acid as an anti-metastatic compound that functions by targeting this post-translational modification. Mechanistically, beyond its canonical pro-apoptotic activity, usnic acid induces ferroptosis through the selective inhibition of CRYAB phosphorylation at serine 59. These findings provide a mechanistic foundation for the development of usnic acid as a potential therapeutic agent for metastatic colorectal cancer, and emphasize the clinical potential of targeting CRYAB phosphorylation and ferroptosis in the management of colorectal cancer liver metastases.