Work

RPL28 mediates sorafenib resistance in hepatocellular carcinoma by downregulating CDC6 expression

Year: 2026

Type: article

Abstract: 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: 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 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, contributing to 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.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1741406

Authors: Yi Shi, Fangfang Chen, Yuanyuan Weng, Hang Zeng, Gang Chen

Institutions: Fujian Medical University, Fujian Provincial Cancer Hospital

Language: English

Topic: Hepatocellular Carcinoma Treatment and Prognosis

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801