@Article{or.2026.087514,
AUTHOR = {Jian Wang, Chunxiu Suo, Yu Xie, Renjun Gu, Nan Lu, Xinyan Zhang, Xiaojuan Liu},
TITLE = {Small Molecule Targeted Therapy for Hepatocellular Carcinoma: From Multikinase Inhibition to Cancer Stem Cell Eradication Strategies},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/28389},
ISSN = {1555-3906},
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.},
DOI = {10.32604/or.2026.087514}
}