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REVIEW

Small Molecule Targeted Therapy for Hepatocellular Carcinoma: From Multikinase Inhibition to Cancer Stem Cell Eradication Strategies

Jian Wang1,#, Chunxiu Suo2,#, Yu Xie3,#, Renjun Gu4, Nan Lu5,*, Xinyan Zhang4,*, Xiaojuan Liu6,*
1 National Administration of Traditional Chinese Medicine Institutional Service Center, Beijing, China
2 Department of Critical Care Medicine, Rongcheng Shidao People’s Hospital (Formerly Rongcheng No.2 People's Hospital), Rongcheng, China
3 PLA Rocket Force Characteristic Medical Center, Beijing, China
4 School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
5 State Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
6 Department of Hepatology and Hematology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an, China
* Corresponding Author: Nan Lu. Email: email; Xinyan Zhang. Email: email; Xiaojuan Liu. Email: email
# These authors contributed equally to this work as the first author

Oncology Research https://doi.org/10.32604/or.2026.087514

Received 17 June 2026; Accepted 11 September 2026; Published online 21 September 2026

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide, posing a significant global health burden. Multikinase inhibitors (MKIs) such as sorafenib and lenvatinib are standard therapies for advanced HCC, yet most patients eventually develop drug resistance and tumor relapse, largely attributed to the presence of cancer stem cells (CSCs). These cells, which possess self-renewal capacity and intrinsic resistance to conventional treatments, drive tumor heterogeneity and recurrence. This review examines the molecular features of HCC CSCs and their regulatory networks, including Wnt/β-catenin, Phosphoinositide 3-kinase (PI3K)/Akt/Mammalian target of rapamycin (mTOR), and Notch signaling pathways. CSCs drive tyrosine kinase inhibitor (TKI) resistance through mechanisms such as Caveolin 1 (CAV1)-mediated dormancy and the CD133/Myosin heavy chain 9 (MYH9)/β-catenin axis, which sustain survival and proliferation despite targeted therapy. Recent preclinical studies have identified small molecule inhibitors targeting CSC-specific pathways and markers, including C504244, 4-MU, bestatin, OSU-CG5, and CL26, which show promise in eradicating CSC populations. Combination strategies that pair TKIs with these agents demonstrate synergistic effects, particularly when delivered via nanoparticle systems, which enhance drug bioavailability and tumor targeting. However, major barriers to clinical translation include CSC heterogeneity, microenvironmental adaptation, and the lack of reliable biomarkers for patient stratification. The shift from multikinase inhibition to CSC eradication represents a promising paradigm for transforming HCC into a more manageable disease, potentially improving long-term outcomes and reducing relapse rates.

Keywords

Hepatocellular carcinoma; cancer stem cells; multikinase inhibitors; drug resistance; small molecule inhibitors; wnt β-catenin pathway; combination therapy

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