Oncofetal dual‑specificity phosphatase 9 drives stem-like properties through ERK1/2-PPARG-SCD axis-mediated lipid metabolism in hepatocellular carcinoma

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.

Key points: Oncofetal reprogramming-based prognostic signature robustly stratifies HCC patient survival across independent cohorts. DUSP9 is identified as a core oncofetal regulator that drives stem-like traits in HCC. Mechanistically, DUSP9 suppresses ERK1/2-phosphorylation, stabilizes PPARG, and transcriptionally activates SCD. The DUSP9-ERK1/2-PPARG-SCD axis remodels lipid metabolism to support proliferation, cell mobility, and sorafenib resistance.

DUSP9; hepatocellular carcinoma; lipid metabolism; oncofetal reprogramming; prognostic signature; stemness.