Lipid deposition promotes YTHDF3-mediated m6A modification of PPARα to facilitate liver metastasis of colorectal cancer

Abstract The liver is a common site for cancer metastasis and a key metabolic organ. Lipid metabolism irregularities are linked to liver metastasis risk, but the mechanisms are not fully understood. Herein, in colorectal liver metastases (CRLM) clinical samples, lipid metabolism was broadly dysregulated, and lipid metabolites accumulated, as shown by integrated transcriptome and lipidomics analyses. Functionally, lipids deposition promotes liver metastasis in vitro and in vivo. Mechanistically, lipid deposition significantly enhances YTHDF3-mediated m6A modification and degradation of PPARα, which is crucial for liver metastasis. This process reduces the β-hydroxybutyrylation of YTHDF3, thereby promoting LLPS and increasing the stability of YTHDF3, which in turn facilitates the progression of CRC and liver metastasis. Furthermore, lipid deposition induces the interaction between STAT3 and YAP, activating YTHDF3 transcription. These two regulatory mechanisms synergize to drive YTHDF3 accumulation in lipid-rich metastatic lesions. In summary, our findings reveal that lipid deposition promotes LLPS-mediated m6A modification and decreases β-hydroxybutyrylation in liver metastasis, offering new strategies for the treatment of CRLM.