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Usnic Acid Inhibits Colorectal Cancer Liver Metastasis by Targeting CRYAB Phosphorylation and Inducing Ferroptosis

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jinlai Wei

PROVIDER: PXD075824 | iProX | Wed Mar 18 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Colorectal cancer (CRC) is one of the most lethal cancers when it progresses to the advanced/metastatic stage. Treatment options for refractory metastatic colorectal cancer (mCRC) are limited. Therefore, there is an urgent need to develop effective treatment methods for metastatic colorectal cancer. In this study, we screened a library of small molecules for inhibitors of CRC recurrence using CRC cell lines and patient-derived organoids (PDOs) from metastatic, heavily pretreated CRC. The in vivo efficacy of LS-1-2 was evaluated in the HCT116 and the resistant HCT8 cell lines, patient-derived xenografts(PDXs) including refractory mCRC, and a liver metastasis mouse model. Biotin pull-down and liquid chromatography tandem-mass spectrometry (LC-MS/MS) were performed to identify proteins that interact with LS-1-2. The genome-wide gene expression and quantitative phosphoproteomic analyses were performed to determine the signaling pathway involved in LS-1-2. Molecular docking, molecular dynamics analysis and cellular thermal shift assays were used to predict and validate the binding sites of LS-1-2 on non-muscle Myosin IIA (NMHC IIA). Our results showed that LS-1-2 exhibited broad antiproliferative effects on a series of CRC cell lines and PDOs. The in vivo anti-tumor efficacy of LS-1-2 was demonstrated across cell line- and patient-derived xenografts and in the liver metastatic CRC model. NMHC IIA was identified as a direct target of LS-1-2, and LS-1-2 competitively inhibited the phosphorylation of NMHC IIA at S1943 and S1714 by CK2. NMHC IIA phosphorylation promoted CRC cell proliferation and invasion, which was reduced by LS-1-2. NMHC IIA phosphorylation-mediated YAP activity induced activation of AKT and inactivation of FOXO3a and was suppressed by LS-1-2. In conclusion, our findings suggest that NMHC IIA phosphorylation can be used as a potential molecular target in CRC metastasis, and that targeting NMHC IIA phosphorylation by LS-1-2 may be a promising strategy for the treatment and prevention of CRC metastasis.

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Usnic Acid Inhibits Colorectal Cancer Liver Metastasis by Targeting CRYAB Phosphorylation and Inducing Ferroptosis

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