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 cancer li...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 cancer liver metastasis(CRLM)clinical samples,lipid metabolism was broadly dysregulated,and lipid metabolites accumulated,as shown by integrated transcriptome and lipidomics analyses.Functionally,lipid 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 theβ-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 decreasesβ-hydroxybutyrylation in liver metastasis,offering new strategies for the treatment of CRLM.展开更多
基金supported by the National Natural Founda tion of China(grant numbers 82130080,82273145,82372042,U24A20726)the Guangdong Basic and Applied Basic Research Foundation(grant numbers 2021A1515010224,2024A1515012816,2023A1515011339).
文摘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 cancer liver metastasis(CRLM)clinical samples,lipid metabolism was broadly dysregulated,and lipid metabolites accumulated,as shown by integrated transcriptome and lipidomics analyses.Functionally,lipid 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 theβ-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 decreasesβ-hydroxybutyrylation in liver metastasis,offering new strategies for the treatment of CRLM.
