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

Area of Science:

• Oncology
• Molecular Biology
• Hepatology

Background:

• The transition from metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) lacks clear mechanistic understanding.
• The role of circular RNAs (circRNAs) as biomarkers or therapeutic targets in MASH/HCC progression remains underexplored.

Purpose of the Study:

• To investigate the role of circRNAs in the progression of MASH to HCC.
• To explore circSMEK1 as a potential biomarker and therapeutic target for MASH/HCC.

Main Methods:

• Integrative transcriptomic analysis of circRNAs in MASH and HCC patient cohorts (n=206).
• Mechanistic studies involving RNA-protein interactions, CRISPR-mediated knockdown, and mouse models (xenograft, PiggyBac).
• Analysis of serum and tissue samples for circSMEK1 levels and correlation with clinical parameters.

Main Results:

• circSMEK1 is significantly downregulated in MASH/HCC tissues and serum, correlating with tumor size, vascular invasion, and survival.
• Mechanistically, circSMEK1 suppresses HCC growth by inhibiting IGF2 transcription via hnRNPK interaction and PI3K/AKT signaling.
• SF3B4 overexpression leads to circSMEK1 depletion; circSMEK1 restoration inhibits tumor growth and metastasis in mice.
• Serum circSMEK1 demonstrates diagnostic value for HCC (AUC=0.790) and potential for early HCC or high-risk MASH detection.

Conclusions:

• circSMEK1 functions as a tumor suppressor in MASH/HCC via the hnRNPK-IGF2-AKT pathway.
• Serum circSMEK1 serves as a non-invasive biomarker for HCC diagnosis and risk stratification in MASH.
• Restoring circSMEK1 presents a novel therapeutic strategy for HCC, potentially combined with IGF2 inhibitors.