WDR4/TRIM28 is a novel molecular target linked to lenvatinib resistance that helps retain the stem characteristics in hepatocellular carcinomas.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with few effective treatment options. Lenvatinib is the first-line therapy for HCC but has only limited clinical benefit. Here, we explored the role and mechanism of the WD repeat domain 4 (WDR4) in lenvatinib resistance to improve clinical benefit. We found that lenvatinib-resistant HCC tissues/cells exhibited increased the N-methylguanosine (mG) modification and WDR4 expression. By a gain/loss of function experiment, we showed that WDR4 promoted HCC lenvatinib resistance and tumor progress both in vitro and in vivo. By proteomics analysis and RNA immunoprecipitation PCR, we found that tripartite motif protein 28 (trim28) was an important WDR4 target gene. WDR4 promoted TRIM28 expression, further affected target genes expression, and thus increased cell-acquired stemness and lenvatinib resistance. Clinical tissue data showed that TRIM28 expression was correlated with WDR4 levels, and the expression of both was positively correlated with poor prognosis. Our study provides new insight into the role of WDR4, suggesting a potential therapeutic target to enhance the lenvatinib sensitivity of HCC.