Abstract
Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC), yet nearly half of treated patients fail to achieve durable benefit, and reliable biomarkers enabling early therapeutic stratification are still lacking. Treatment response is typically assessed by imaging one month after TACE and at three-month intervals, potentially delaying timely access to alternative therapies in non-responding patients. Circulating microRNAs (miRNAs) represent promising biomarkers due to their stability in body fluids and ease of detection. Here, we evaluated circulating miR-22 as an early predictor of TACE non-responder status and as a mechanistically relevant therapeutic target. Circulating miR-22 levels were measured by microarray and quantitative RT-PCR in three independent cohorts of early-to-intermediate-stage HCC patients undergoing TACE. Circulating miR-22 increased significantly in non-responders as early as 48 h after treatment, and fold changes consistently predicted treatment failure across two independent validation cohorts. Mechanistically, we identified the G2/M checkpoint kinase WEE1 as a direct functional target of miR-22. Modulation of the miR-22/WEE1 axis affected cell-cycle progression, proliferation, apoptosis, and DNA damage response in HCC cell lines and xenograft models. Under hypoxia-mimicking conditions combined with doxorubicin exposure, pharmacological inhibition of WEE1 induced mitotic catastrophe in highly proliferative miR-22-silenced cells. Collectively, these findings identify early post-TACE elevation of circulating miR-22 as a biomarker of non-response and highlight the miR-22/WEE1 axis as a potential target for precision treatment strategies in HCC.