Collectively, these findings establish a mechanistic axis in which miR-149-3p-mediated suppression of TIMP3 promotes sorafenib resistance, EMT, and stemness in HCC. This work identifies TIMP3 as a pivotal determinant of tumor aggressiveness and suggests restoring TIMP3 or targeting downstream pathways as strategies to overcome resistance.

Tumor-intrinsic activation of the NRF2-COX2-PGE₂ axis drives immune cold TMEs and mediates Atez/Bev resistance in HCC. Targeting this pathway may enhance efficacy, and plasma PGE₂ represents a non-invasive biomarker for stratification.

Insertion sites located in Hinge Region(HR)/β1 domain and juxtamembrane domain (JMD) derived significantly greater benefit from early FLT3 inhibitor therapy(primarily sorafenib), showing significantly prolonged overall survival...In the era of FLT3-ITD targeted drug therapy combined with transplantation, the insertion site of FLT3-ITD based on high throughput sequencing results helps predict the efficacy of FLT3 inhibitors. Integrating white blood cell count with HR/β1 insertion site can identify a high-risk patient subgroup likely to benefit from FLT3 inhibitor therapy.

Furthermore, in an in vivo xenograft model, B10 (40 mg/kg) achieved a tumor growth inhibition rate of 64.2%, outperforming the standard drug sorafenib...This chemical probe enabled us to identify fibroblast growth factor receptor 3 (FGFR3) as a direct target of B10 and to elucidate its role in suppressing the FGFR3/PI3K/AKT signaling pathway. Collectively, this study not only presents B10 as a highly promising candidate for HCC treatment derived from a natural product scaffold, but also identifies FGFR3 as a novel therapeutic target in HCC, thereby providing an innovative and generalizable platform for target deconvolution and mechanistic investigation of natural product-based agents.

CD73 expression was observed in 45.8% of patients whose disease was under control with sorafenib, while 80% of patients who did not respond to sorafenib showed CD73 expression (p = 0.02).ConclusionsPositive lymphocyte activation gene 3 expression was correlated with better survival in patients with advanced or metastatic hepatocellular carcinoma. In addition, CD73 expression in patients with advanced or metastatic hepatocellular carcinoma was a negative predictive factor in those receiving sorafenib.

This strategy restores ferroptosis and induces apoptosis in sorafenib-resistant HCC by suppressing SLC7A11, leading to marked tumor inhibition. Our study demonstrates an ML-assisted LNP optimization strategy, advancing precision RNA therapeutics to overcome resistance in refractory liver cancer.

For example, anticancer therapies targeting vascular endothelial growth factor activity have been effective in blocking pro-angiogenic and pro-growth signals, including receptor tyrosine kinase inhibitors (e.g., Sunitinib and Sorafenib) and monoclonal antibodies (e.g., Bevacizumab). The capacity of heparin to promote the association of FGF2 with its cognate receptors (FGFRs) led to the degradation of the entire receptor-ligand complex, thereby reducing the availability of FGFRs at the cancer cell surface, which are necessary for sustained pro-oncogenic signaling. These findings highlight the potential of GLYTACs as an alternative to existing growth factor-blocking anticancer therapies and as a strategy to reshape the extracellular signaling environment of tumors.

Interestingly, sorafenib-induced apoptosis in HepG2 cells was repressed by siADAR1, but this repression was not observed in HepG2 CYCS 3'-UTR-deleted cells. Collectively, this study clarified that ADAR1 upregulates CYCS translation by inhibiting stress granule formation and thereby can facilitate anticancer agent-induced apoptosis.

This study provides insights into the molecular mechanisms underlying PAAD and establishes a theoretical foundation for the development of CAF-targeting therapeutic strategies.

P1, N=91, Completed, BeiGene | Trial completion date: Feb 2026 --> Oct 2025 | Active, not recruiting --> Completed

SYP restored sorafenib sensitivity in resistant cells through G6PD inhibition. SYP enhances bevacizumab efficacy by targeting angiogenesis, ferroptosis, and G6PD-mediated resistance, providing a rationale for integrating traditional and modern therapies in HCC management. These findings highlight the value of network pharmacology in elucidating TCM mechanisms and support further clinical evaluation.

Notably, decursin retained its efficacy in sorafenib-resistant HCC cells. Collectively, these findings identify decursin as a ferroptosis-inducing agent with therapeutic potential in HCC.