ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
RPL28 mediates sorafenib resistance in hepatocellular carcinoma by downregulating CDC6 expression
Provisionally accepted
- Fujian Provincial Cancer Hospital, Fuzhou, China
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Aim: Sorafenib is a milestone targeted therapy for advanced hepatocellular carcinoma (HCC), yet resistance to this agent severely limits its clinical efficacy. The molecular mechanisms underlying sorafenib resistance are incompletely understood. Ribosomal proteins (RPs) have been increasingly implicated in cancer progression and drug resistance, but the role and mechanism of ribosomal protein L28 (RPL28) in sorafenib resistance in HCC remains unexplored. Methods: We investigated the functional role of RPL28 in sorafenib-resistant HCC using HepG2 and HCCLM3 cell models. RPL28 was silenced by siRNA, and effects on cell proliferation, migration, and sorafenib sensitivity were assessed by CCK-8, migration assays, and IC50 determination. Integrated transcriptomic and proteomic analyses were performed to delineate downstream pathways. The expression of immune-related proteins and key targets was validated by Western blotting. Results: RPL28 expression was significantly reduced at both mRNA and protein levels in knockdown cells of sorafenib-resistant HepG2 and HCCLM3. RPL28 knockdown inhibited proliferation and migration and enhanced sensitivity to sorafenib in resistant HCC cells. Transcriptomic and proteomic analyses identified CDC6 as a key downstream target of RPL28. CDC6 expression was consistently decreased in RPL28 KD cells, while EGFR and TRAF6 remained unchanged. GO and KEGG pathway enrichment revealed that RPL28 modulates pathways involved in DNA replication, immune regulation, and metabolic adaptation. Notably, no significant changes were observed in MHC-I and PD-L1 expression following RPL28 knockdown. Conclusions: Our findings demonstrate that RPL28 contributes to sorafenib resistance in HCC by upregulating CDC6, promoting tumor proliferation and drug resistance. The newly identified RPL28-CDC6 axis represents a novel mechanism of resistance and a potential therapeutic target to overcome treatment limitations in HCC.
Keywords: CDC6, Hepatocellular Carcinoma, proliferation, Ribosomal proteins L28 (RPL28), Sorafenib resistance
Received: 07 Nov 2025; Accepted: 05 Jan 2026.
Copyright: © 2026 Shi, Chen, Weng, Zeng and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Gang Chen
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