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

Overview

This study reveals how lipid metabolism dysregulation promotes colorectal cancer liver metastasis (CRLM) through a novel YTHDF3-mediated mechanism involving m⁶A RNA modification and liquid-liquid phase separation.

Key Findings

Lipid Metabolism & Clinical Impact: • Significant lipid accumulation observed in CRLM tissues with upregulated lipid synthesis and downregulated catabolism • High YTHDF3 expression correlated with poor survival (26 vs. 44 months median survival) • High-fat diet accelerated tumor progression and metastasis in mouse models

Molecular Mechanism: • Lipid deposition enhances YTHDF3 expression through dual mechanisms: transcriptional activation via STAT3-YAP pathway and post-translational stabilization • YTHDF3 promotes m⁶A modification of PPARα mRNA, leading to its degradation • Reduced PPARα decreases fatty acid oxidation metabolites (acetyl-L-carnitine and β-hydroxybutyrate) • β-hydroxybutyrate normally induces β-hydroxybutyrylation of YTHDF3, promoting its degradation—this protective feedback is disrupted by lipid accumulation

Novel LLPS Discovery: • Lipid deposition dramatically increases YTHDF3 liquid-liquid phase separation and condensate formation • Enhanced YTHDF3 co-localization with lipid droplets drives metastatic progression • N-terminal domain (1-416 aa) essential for phase separation dynamics

Therapeutic Implications

• Time-restricted feeding and PPARα agonist fenofibrate significantly inhibited metastasis • Targeting the YTHDF3-PPARα axis represents a promising therapeutic strategy • Metabolic interventions to reduce lipid deposition may prevent CRLM

Significance

This research establishes a critical link between dietary lipids, epigenetic regulation, and cancer metastasis, offering new mechanistic insights and therapeutic targets for preventing colorectal cancer liver metastasis through metabolic modulation.