CircSMEK1 Suppresses HCC via the hnRNPK‐IGF2‐AKT Axis: A Diagnostic Biomarker and Therapeutic Target

CircSMEK1 is downregulated in MASH/HCC and predicts poor prognosis. It suppresses tumor progression by promoting hnRNPK ubiquitination and inhibiting the IGF2/PI3K/AKT axis, while its loss activates immunosuppressive cancer‐associated fibroblasts. Serum circSMEK1 serves as a non‐invasive diagnostic biomarker, and its restoration potently inhibits HCC growth and metastasis in vivo. Abstract The mechanism underlying metabolic dysfunction‐associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) is elusive, and whether circRNA can serve as biomarker or therapeutic target for MASH/HCC needs to be systematically explored. Integrative transcriptomic analysis of circRNA from MASH and HCC were performed. Multi‐cohort analyses of serum and tissues from MASH and HCC patients (n = 206) were conducted. Mechanisms are explored via RNA‐protein interaction assays, CRISPR‐mediated knockdown, and xenograft/PiggyBac‐mediated mice models. circSMEK1 is significantly decreased in MASH/HCC tissues and serum, correlating with tumor size, vascular invasion, and overall survival. Mechanistically, nuclear circSMEK1 binds hnRNPK, promoting its ubiquitin‐mediated degradation, suppressing IGF2 transcription and PI3K/AKT signaling. Loss of circSMEK1 elevated autocrine IGF2 in HCC promoting tumor growth, also activated AKT in cancer‐associated fibroblasts through paracrine, fostering an immunosuppressive microenvironment. SF3B4 overexpression drove circSMEK1 depletion in HCC. In murine models, circSMEK1 restoration inhibited tumor growth and metastasis. circSMEK1 is a tumor‐suppressor in MASH/HCC through the hnRNPK‐IGF2‐AKT axis. The serum level of circSMEK1 has non‐invasive diagnostic value for HCC (AUC = 0.790), as well as potential diagnostic utility for early HCC or high‐risk MASH, owing to its key role in bridging MASH to HCC progression. Restoring of circSMEK1, alone or combined with IGF2 inhibitors, proposing a novel therapeutic strategy for HCC. CircSMEK1 is downregulated in MASH/HCC and predicts poor prognosis. It suppresses tumor progression by promoting hnRNPK ubiquitination and inhibiting the IGF2/PI3K/AKT axis, while its loss activates immunosuppressive cancer-associated fibroblasts. Serum circSMEK1 serves as a non-invasive diagnostic biomarker, and its restoration potently inhibits HCC growth and metastasis in vivo. Abstract The mechanism underlying metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) is elusive, and whether circRNA can serve as biomarker or therapeutic target for MASH/HCC needs to be systematically explored. Integrative transcriptomic analysis of circRNA from MASH and HCC were performed. Multi-cohort analyses of serum and tissues from MASH and HCC patients ( n = 206) were conducted. Mechanisms are explored via RNA-protein interaction assays, CRISPR-mediated knockdown, and xenograft/PiggyBac-mediated mice models. circSMEK1 is significantly decreased in MASH/HCC tissues and serum, correlating with tumor size, vascular invasion, and overall survival. Mechanistically, nuclear circSMEK1 binds hnRNPK, promoting its ubiquitin-mediated degradation, suppressing IGF2 transcription and PI3K/AKT signaling. Loss of circSMEK1 elevated autocrine IGF2 in HCC promoting tumor growth, also activated AKT in cancer-associated fibroblasts through paracrine, fostering an immunosuppressive microenvironment. SF3B4 overexpression drove circSMEK1 depletion in HCC. In murine models, circSMEK1 restoration inhibited tumor growth and metastasis. circSMEK1 is a tumor-suppressor in MASH/HCC through the hnRNPK-IGF2-AKT axis. The serum level of circSMEK1 has non-invasive diagnostic value for HCC (AUC = 0.790), as well as potential diagnostic utility for early HCC or high-risk MASH, owing to its key role in bridging MASH to HCC progression. Restoring of circSMEK1, alone or combined with IGF2 inhibitors, proposing a novel therapeutic strategy for HCC. Advanced Science, Volume 12, Issue 48, December 29, 2025.