This study elucidates the critical role of CRYAB phosphorylation in driving the progression of liver metastasis in colorectal cancer, and validates that usnic acid exerts anti-metastatic activity by modulating this post-translational modification. Mechanistically, in addition to its established pro-apoptotic function, usnic acid triggers ferroptosis via suppressing CRYAB phosphorylation at the S59 site. These results construct a mechanistic basis for usnic acid as a promising therapeutic candidate against metastatic colorectal cancer, underscoring the translational potential of targeting CRYAB phosphorylation and ferroptosis for the clinical intervention of colorectal cancer liver metastases.