{
  "abstract": "Background Colorectal sessile serrated lesions (SSLs) are important precursor lesions of colorectal cancer (CRC), yet their molecular pathogenesis remains poorly understood. Agrin (AGRN), a heparan sulfate proteoglycan implicated in cancer progression, has not been investigated in SSLs. This study aimed to characterize AGRN expression in SSLs, define its functional roles in BRAFV600E-mutant RKO cells, and explore the molecular mechanisms linking endoplasmic reticulum stress (ERS), lipid metabolism, and ferroptosis.Methods We integrated public single-cell RNA sequencing (scRNA-seq) data comprising 65,088 epithelial cells from normal colon (NL), hyperplastic polyps (HP), SSLs, traditional adenomas (TA), and tubulovillous adenomas (TVA), together with an in-house scRNA-seq cohort of 82,744 cells, to map AGRN expression. Bulk RNA sequencing was performed on 47 clinical samples (NL, n=12; HP, n=13; SSL, n=22), with validation in three independent Gene Expression Omnibus datasets. Stable AGRN-knockdown RKO cells were established and validated by quantitative reverse-transcription polymerase chain reaction and western blotting. Cell proliferation and migration were assessed by colony formation, Cell Counting Kit-8, and wound-healing assays. RNA sequencing, untargeted metabolomics, ERS/ferroptosis-related western blotting, and lipid metabolite profiling were performed to investigate downstream mechanisms.Results scRNA-seq showed that AGRN was specifically enriched in SSL-derived serrated-specific cells and reached its highest expression in SSLs compared with NL, HP, TA, and TVA (p<0.001, IDDF2026-ABS-0272 Figure 1). Bulk RNA sequencing and external validation confirmed AGRN upregulation in SSLs (fold change=2.1 vs. NL, p=1.27×10−14), and high AGRN expression was associated with worse CRC survival (hazard ratio=1.25, 95% confidence interval=1.01-1.56, p=0.039, IDDF2026-ABS-0272 Figure 2). AGRN knockdown significantly inhibited the proliferation and migration of RKO cells (p<0.001, IDDF2026-ABS-0272 Figure 3). Transcriptomic analysis revealed enrichment of autophagy, TOR, and Hippo pathways (IDDF2026-ABS-0272 Figure 4), while metabolomics demonstrated dysregulated lipid metabolism, including linoleic acid and glutathione metabolism (IDDF2026-ABS-0272 Figure 5). ERS/ferroptosis markers and key lipid metabolites were altered after AGRN knockdown (IDDF2026-ABS-0272 Figure 6), suggesting that AGRN is required to maintain endoplasmic reticulum and lipid homeostasis and to limit ferroptosis-related vulnerability.Conclusions AGRN is a novel SSL-associated biomarker that promotes colon cancer cell proliferation and migration, potentially by maintaining endoplasmic reticulum and lipid homeostasis. These findings highlight AGRN as a potential therapeutic target for blocking progression from SSL to CRC.Abstract IDDF2026-ABS-0272 Figure 1Abstract IDDF2026-ABS-0272 Figure 2Abstract IDDF2026-ABS-0272 Figure 3Abstract IDDF2026-ABS-0272 Figure 4Abstract IDDF2026-ABS-0272 Figure 5Abstract IDDF2026-ABS-0272 Figure 6",
  "authors": [
    {
      "affiliations": [
        "Shanghai Tenth People’s Hospital, Tongji University School of Medicine, China"
      ],
      "name": "Junnan Hu"
    },
    {
      "affiliations": [
        "Shanghai Tenth People’s Hospital, Tongji University School of Medicine, China"
      ],
      "name": "Liangtang Zeng"
    },
    {
      "affiliations": [
        "Shanghai Tenth People’s Hospital, Tongji University School of Medicine, China"
      ],
      "name": "Feng Liu"
    }
  ],
  "title": "IDDF2026-ABS-0272 Agrn promotes sessile serrated lesion progression by maintaining endoplasmic reticulum and lipid homeostasis",
  "uid": "1ed3b42c-fb27-5049-a25e-215dfb716aa0"
}