{
  "abstract": "Background Intrahepatic cholangiocarcinoma (iCCA) is a highly invasive malignancy characterized by marked intratumoral and microenvironmental heterogeneity. However, how metabolic reprogramming in malignant epithelial cells shapes a pro-invasive multicellular niche remains unclear. We aimed to define the biological features of the PSPH-high tumor state in iCCA and to determine how phosphoserine phosphatase (PSPH)-mediated serine metabolic reprogramming remodels the tumor ecosystem through fibronectin 1 (FN1)-integrin signaling.Methods Paired tumor and adjacent tissues from patients with iCCA were analyzed by single-cell RNA sequencing, malignant epithelial cell-state dissection, cell-cell communication analysis, and spatial validation. In vitro, PSPH was genetically manipulated in iCCA cells to evaluate the effects of serine metabolism on migration, invasion, and epithelial-mesenchymal transition (EMT). Co-culture and organoid models were used to determine how tumor cell-intrinsic serine metabolic reprogramming modulates tumor-associated macrophages (TAMs), hepatic stellate cells (HSCs), and endothelial cells. In vivo, PSPH-deficient mouse iCCA models combined with single-cell analysis were used to assess niche remodeling. Mechanistic studies integrated metabolic, biochemical, and transcriptional assays to define how PSPH regulates FN1 expression.Results We identified a PSPH-high malignant epithelial subpopulation enriched for serine metabolism, EMT, and invasion-related transcriptional programs. Functionally, PSPH promoted iCCA cell migration, invasion, and EMT. Co-culture assays further showed that PSPH-high tumor cells drove TAMs, HSCs, and endothelial cells toward inflammatory, matrix-remodeling, and angiogenic phenotypes, respectively. Cell-cell communication analysis indicated that FN1-integrin signaling represents an important downstream intercellular communication route associated with the PSPH-high state, which was further spatially validated in patient tissues. In vivo, PSPH deficiency markedly suppressed tumor invasion and impaired pro-tumor microenvironmental programs. Mechanistically, PSPH-mediated serine metabolic reprogramming enhanced ZFP64 succinylation, thereby promoting FN1 transcriptional activation and facilitating pro-invasive signaling from tumor cells to stromal recipient cells.Conclusions PSPH is a key metabolic driver of iCCA progression. By linking serine metabolic reprogramming to ZFP64 succinylation-dependent FN1 transcription, PSPH establishes and amplifies an FN1-integrin multicellular niche that promotes tumor invasion. Targeting this pathway may represent a therapeutic strategy for iCCA.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, China"
      ],
      "name": "Shikai Qiao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, China"
      ],
      "name": "Luying Zhao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, China"
      ],
      "name": "Shujing Xu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, China"
      ],
      "name": "Changqing Yang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, China"
      ],
      "name": "Jing Li"
    }
  ],
  "title": "IDDF2026-ABS-0406 PSPH-mediated serine metabolic reprogramming drives an FN1–integrin multicellular niche through ZFP64 succinylation in intrahepatic cholangiocarcinoma",
  "uid": "d7216c5c-082d-501f-b53d-c33d55b29f42"
}