ArticleJHEP reports : innovation in hepatology2026
SREBP-driven lipogenesis coupled with ferroptosis resistance as a therapeutic target in PTEN-loss extrahepatic cholangiocarcinoma.
Article in JHEP reports : innovation in hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsExtrahepatic cholangiocarcinoma (eCCA) is an aggressive biliary tract cancer (BTC) with limited therapeutic options and actionable genetic alterations. Although PTEN loss and PI3K pathway activation are common in eCCA, their roles in disease pathogenesis and therapeutic vulnerability remain unclear. Therefore, we aimed to establish clinically relevant mouse models of PTEN loss-driven eCCA and identify novel therapeutic strategies.
methodsTo investigate eCCA development and the underlying mechanisms, we generated CK19-Cre
resultsPTEN loss alone was insufficient for tumorigenesis, whereas combined deletion of PTEN and TGFβR2 induced periductal infiltrating-type eCCA originating from the peribiliary glands. In contrast, PTEN loss and oncogenic Kras activation predominantly generated intraductal-growing tumors with broader biliary involvement. These included intrahepatic cholangiocarcinoma (iCCA) and gallbladder cancer (GBC). RNA sequencing revealed that SCAP/SREBP-mediated lipogenesis was consistently activated in the PTEN loss-driven eCCA models. Genetic ablation of SCAP markedly suppressed eCCA development (p <0.0001) but exacerbated iCCA, indicating the need for alternative therapeutic approaches. SREBP-driven lipogenesis increased the synthesis of polyunsaturated phospholipids and concomitantly induced GPX4, thereby conferring resistance to ferroptosis. GPX4 inhibition suppressed eCCA (p = 0.002) and GBC development without exacerbating iCCA. Consistently, PTEN-deficient human BTC cell lines, including CRISPR-Cas9-engineered models, exhibited increased vulnerability to GPX4 inhibition. Furthermore, clinical eCCA samples (n = 182) confirmed the coordinated activation of the PI3K, SREBP, and ferroptosis pathways.
conclusionsDistinct oncogenic alterations shape the histological and anatomical diversity of BTC. PTEN loss-driven eCCA critically depends on SCAP/SREBP-mediated lipid reprogramming and GPX4-dependent ferroptosis resistance, indicating the therapeutic potential of ferroptosis induction. IMPACT AND IMPLICATIONS: This study provides a scientific rationale for the stratification of extrahepatic cholangiocarcinoma (eCCA) based on oncogenic context. Our findings demonstrate that PTEN loss is associated with shared lipid metabolic features, whereas additional genetic alterations determine histological growth patterns and anatomical distribution. We identified ferroptosis resistance as a key downstream feature of PTEN-deficient eCCA. Although further validation is required, these findings provide a theoretical basis for further exploring ferroptosis-based therapeutic approaches for genetically defined subsets of biliary tract cancer.
Indexed as
Identifiers
42667985What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.