drug pressure drove clonal selection and genomic drift。

its dynamic changes and core regulators remain unclear. Defining the clonal evolution and metabolic drivers of acquired resistance is essential for identifying therapeutic targets. METHODS: Forty-six CRC PDOs were established and subjected to long-term， ICGC-ARGO，。

indicating PDOs maintain tumor representativeness during long-term culture. Copy-number alterations of dominant clones correlated with gene expression， and restored chemosensitivity. FAO inhibition reversed resistance in CIDEA-overexpressing cells. In vivo xenografts confirmed that CIDEA knockdown improved chemosensitivity， FABP1。

with ~60% of mutations retained in late stages， stemness phenotype。

ABSTRACT BACKGROUND: Chemoresistance remains a major challenge to long-term survival in colorectal cancer (CRC). Although lipid metabolic reprogramming is a key adaptation under sustained drug pressure， suggesting a gene-dosage effect. Multi-omics analyses revealed marked upregulation of CIDEA in resistant PDOs， along with activation of MAPK and PI3K-Akt pathways. Across TCGA。

and recurrent cohorts。

and transcriptional remodeling. Multi-cohort validation used TCGA。

CIDEA overexpression promoted lipid droplet accumulation and enhanced fatty acid oxidation (FAO)， downregulated lipid metabolic genes。

and recurrent tumor samples from our institution. Functional assays-including lipid metabolic activity， clonal evolution。

CD36， while CIDEA-driven resistance was reversed by FAO inhibition. CONCLUSIONS: This study delineates the clonal evolution and lipid metabolic remodeling underlying acquired chemoresistance in CRC and identifies CIDEA as a key driver that promotes resistance through lipid droplet accumulation and enhanced FAO， driving chemoresistance。

high CIDEA expression was associated with advanced stage and higher recurrence. Functionally， whereas CIDEA knockdown reduced FAO。

followed by overexpression and knockdown PDO models to evaluate in vivo effects using xenografts. RESULTS: Resistant PDOs exhibited denser and more irregular structures with reduced gland-like morphology. Early-stage PDOs retained ~80% of the mutational landscape of primary tumors; with prolonged induction， ACACB。

ICGC-ARGO， accompanied by lipid metabolic remodeling and increased expression of FASN， highlighting its therapeutic potential. Key words: Colorectal cancer; Chemoresistance; Patient-derived organoids; Clonal evolution; Lipid metabolic reprogramming ， dose-escalating FOLFOX induction to generate resistance models. Whole-exome sequencing (WES) and RNA-seq were performed before and after induction to assess genomic stability， and chemosensitivity analyses-were performed for candidate genes。

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