Background: Oncofetal reprogramming—the reactivation of fetal-like gene programmes in malignant cells—has been implicated in the progression and stemness of hepatocellular carcinoma (HCC), yet its protein landscape and connection to tumour stemness remain incompletely defined.
Methods: We integrated multi-omics datasets to derive an oncofetal reprogramming-based prognostic signature (oncoScore) and validated it across multiple independent HCC cohorts. Candidate oncofetal proteins were validated in murine fetal liver and HCC tissue microarrays. Functional characterization of dual-specificity phosphatase 9 (DUSP9) was performed using gain- and loss-of-function studies, including sphere and colony formation, proliferation, migration and invasion assays, sorafenib resistance testing, and limiting-dilution tumourigenicity assays. Mechanistic studies employed Oil Red O staining, co-immunoprecipitation, chromatin immunoprecipitation, pharmacologic inhibition and genetic rescue experiments.
Results: The oncoScore demonstrated robust prognostic value across multiple independent HCC cohorts. DUSP9 emerged as a key regulator of stemness, promoting self-renewal and aggressive phenotypes, enhancing sphere and colony formation, proliferation, migration, invasion, sorafenib resistance, and tumourigenicity. Mechanistically, DUSP9 drives lipid metabolism by upregulating stearoyl-CoA desaturase (SCD) through the ERK1/2peroxisome proliferator-activated receptor gamma (PPARG) signalling axis.
Conclusion: Our results establish the oncoScore as a reliable prognostic marker for HCC and identify a DUSP-9ERK1/2-PPARG-SCD pathway that links lipid metabolism to stemness. Targeting the oncofetal protein DUSP9 may offer a therapeutic avenue for aggressive, stemness-driven HCC.
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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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