Our study identified C/EBP-β as a key effector of the terminal pro-apoptotic ER stress response. While the direct clinical application of TM is limited by its systemic toxicity, these findings highlight the clinical translational potential of targeting the ER stress-C/EBP-β axis, offering a novel combination therapeutic strategy for patients with acquired sorafenib resistance.

Our results show that YBX1 overexpression confers sorafenib resistance in HCC...In vivo studies demonstrated that inhibiting YBX1 with the small-molecule SU056 reduces tumor size. Thus, YBX1 is a promising target for extending drug resistance in HCC.

The treatment-dependent role of GRX1, which is protective in untreated tumors but can promote sorafenib resistance in treated cancers, establishes it as a critical ferroptosis-suppressing mediator and a potential therapeutic target for overcoming sorafenib resistance in RCC.

Additional analyses assessed endoglin/CD105 co-expression, paired primary-metastatic samples (n=41), and associations with adjuvant sorafenib therapy...As a conclusion, P21⁺/MCM2⁻ cell count is a robust biomarker that refines relapse risk stratification in ccRCC and identifies patients who may not benefit from adjuvant tyrosine kinase inhibitor therapy. High levels of these non-proliferative, senescent-like cells suggest tumour dormancy and a more favourable outcome without treatment.

Our study revealed that NDRG2 mediates the ubiquitination and degradation of ACC1 through recruiting COP1. Thus, targeting the NDRG2-ACC1 axis or its combination with sorafenib may be a novel potential strategy for HCC therapy.

In mice, significant reductions in the growth of subcutaneous tumors relative to controls were observed, and it is well-tolerated when compared to Doxorubicin and Sorafenib. Transcriptomics analysis using RNA-Seq revealed that genes involved in regulating cell death, cell proliferation, and cellular processes were enriched in a time- and dose-dependent manner. Overall, the cathepsin inhibitor appears to be a promising starting point for further investigation as an antiproliferative agent.

Since the approval of sorafenib in 2007, an increasing number of treatment regimens have demonstrated encouraging survival benefits in first-line treatment of advanced HCC...Our study is expected to inform clinical guidelines and support personalized therapeutic decisions for advanced HCC. https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420251126975.

KSR1 knockdown did not substantially affect ppERK responses to Type I½ RAF inhibitor (Encorafenib) in both cell types, whereas ppERK sensitivity slightly decreased for Type II RAFi (TAK-632) in MCF7 cells, aligning with simulations. The efficacy of MEKi (Cobimetinib) slightly increased in MCF7 cells following KSR1 knockdown but slightly decreased in PSN1 cells where higher MEKi concentrations were required to suppress ERK signaling, as predicted by the model. Our computational models predict, and experiments validate that in RAS-mutant cells, two conformation-specific RAF inhibitors used in combination suppress the ERK pathway more effectively than a combination of MEK and RAF inhibitors irrespective of KSR1 levels.

Furthermore, drug sensitivity analysis linked SLC25A39 to a broader spectrum of pharmacological agents beyond sorafenib. Collectively, our findings not only reinforce SLC25A39 as a therapeutic target but, for the first time, reposition it as a potential modulator at the intersection of tumor metabolism, epigenetics, and immunology in HCC, offering a rationale for its inhibition, particularly combined with immunotherapy.

Several derivatives exhibited micromolar cytotoxic activity, with compound 14 emerging as the most active against HepG-2 cells (IC50 = 7.84 ± 0.5 µM), showing cytotoxic activity comparable to that of sorafenib (IC50 = 9.18 ± 0.6 µM) and demonstrating favorable selectivity toward normal WI-38 cells (IC50 = 67.75 ± 3.6 µM)...Molecular docking and MD simulations supported a stable binding mode within the VEGFR-2 active site. This integrated framework highlights compound 14 as a selectively active VEGFR-2-oriented anticancer candidate scaffold with a favorable selectivity profile, supported by experimental and computational analyses, warranting further lead optimization.

Additionally, on sorafenib-induced ferroptosis in HCC cells, TF partially reversed the effects of PAEP knockdown. Our research indicates that PAEP may be a potential biomarker for predicting sorafenib resistance in HCC and disruption of PAEP expression may be a potential cancer-directed therapeutic option for HCC.

Our findings identify YEATS2 as a critical mediator of TGF-β1-driven adaptive resistance to sorafenib in HCC through functional activation of TAK1 signaling. Our findings identify the YEATS2-TAK1 axis as a mechanistically relevant pathway underlying TGF-β1-conditioned adaptive resistance to sorafenib in HCC.