Hepatic niche driven metabolic-epigenetic reprogramming mediates metastatic colonization through liver progenitor like plasticity

Background Liver metastasis is a major cause of mortality in small cell lung cancer (SCLC), but the organ-specific cues that enable metastatic colonization are poorly understood. We hypothesized that the hepatic microenvironment promotes a stem-like, high-plasticity state required for metastatic outgrowth. Methods We analyzed patient-derived SCLC liver metastases using RNA-seq, ATAC-seq, and metabolomics, combined with spatial transcriptomics and orthotopic liver colonization models. Regional hypoxia, HIF1alpha signaling, and metabolic flux were assessed by protein quantification and 13C-glucose tracing. Functional studies included pharmacological ACLY inhibition (SB204990) and CRISPR-mediated ACLY knockout in vivo. Results Across patient specimens and in vivo models, metastatic SCLC cells in the liver adopted a distinct stem-like transcriptional state, marked by activation of regenerative programs and chromatin accessibility at stemness loci (HNF1A, HNF4A, SOX9, ATF3). Spatial profiling revealed that tumor cells adjacent to hepatocytes experienced localized hypoxia, resulting in HIF1alpha stabilization and the transcriptional induction of ACLY, a key enzyme that generates nuclear acetyl-CoA. ATP-citrate lyase (ACLY)-dependent generation of nuclear acetyl-CoA, driving histone hyperacetylation and chromatin remodeling at liver-lineage transcription factors HNF1A, HNF4A, and SOX9. Liver-metastatic cells undergo glycolytic reprogramming, a metabolic shift that parallels hepatocyte regeneration during liver injury, providing acetyl-CoA and biosynthetic precursors to support epigenetic remodeling and lineage adaptation. Similar progenitor-like hepatic plasticity is observed across other epithelial cancers with liver tropism, including breast, colon, and non-small cell lung cancers, indicating a conserved mode of metastatic adaptation. ALY activity mediated histone hyperacetylation and epigenetic remodeling required for the stem-like state. ACLY was functionally essential. Pharmacologic ACLY inhibition blocked the induction of stem-like programs, reduced histone acetylation, and growth rate of liver metastatic cells. CRISPR-ACLY knockout prevented the acquisition of the reprogrammed phenotype. Similar hepatic niche-induced stemness signatures were observed in liver metastases from breast, colon, and NSCLC, suggesting a conserved mechanism across epithelial cancers. Conclusions The liver microenvironment actively promotes metastatic competency by inducing a HIF1alpha-ACLY-acetyl-CoA-driven stem-like state in disseminated tumor cells. ACLY inhibition disrupts this metabolic-epigenetic reprogramming and markedly suppresses liver metastatic outgrowth, highlighting ACLY as a tractable therapeutic target for liver metastasis.