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.