In summary, our results demonstrated that HED synergistically promoted the anti-cancer effects of SOR on HCC cells by suppressing SLC7A11 expression, thereby triggering ferroptosis. These results suggest that HED represents a promising strategy to overcome SOR resistance and offers a viable therapeutic approach to improve SOR efficacy in patients with resistant HCC.

In vivo, the tumor inhibition rate reached 58.67%, superior to free CTD and sorafenib, with 100% 14-day survival and no significant abnormalities in serum biochemistry or histopathology. Pharmacokinetic analysis showed prolonged elimination half-life (2.54 h) and a 3.2-fold increase in area under the blood concentration-time curve versus unmodified CSLNs. GA-FA-CSLNs represent a promising actively targeted nanoplatform that enhances CTD antitumor efficacy against HCC via EphB4 pathway inhibition while reducing systemic toxicity, offering a potential strategy for targeted HCC therapy.

Artificial intelligence and machine learning may further support resistance-pattern prediction, patient stratification, nanoplatform selection, and formulation optimization. Overall, sorafenib nanomedicine may integrate drug delivery optimization, resistance intervention, and patient stratification into a unified therapeutic framework with improved mechanistic specificity and translational potential for sorafenib-resistant HCC.

In conclusion, AFP activates the PI3K/AKT signalling pathway to augment aerobic glycolysis in HCC cells, leading to HCC resistance to sorafenib. Inhibition of AFP expression and targeting of PKM2 may represent a novel approach for clinically reversing sorafenib tolerance in HCC patients.

Clinically, elevated TSC22D4 expression correlates with advanced disease stage and poor patient survival. In conclusion, TSC22D4 promotes ccRCC progression and sorafenib resistance by activating the KEAP1-NRF2-SLC7A11 axis and suppressing ferroptosis, highlighting TSC22D4 as a potential therapeutic target in ccRCC.

This molecule exhibited robust anti-proliferative activity across multiple HCC cell lines (HepG2, Hep3B, and Huh7), surpassing both the parent ICA-II and the positive control Sorafenib...Compound 3b administration markedly suppressed tumor growth without significant body weight loss or obvious histopathological abnormalities in major organs under the tested conditions, notably outperforming the clinically approved agent Icaritin. Preliminary pharmacokinetic studies further demonstrated that 3b achieved robust systemic exposure and a prolonged retention time following intravenous administration. Overall, our work provides a successful structural optimization rationale for ICA-II and advances 3b as a safe, EGFR-modulating lead compound for HCC intervention.

ETV4 is a key gene connecting the RAF/MER/ERK pathway and the MMP family in tumor growth and development, especially in HCC. This study provides functional and mechanistic evidence suggesting that ETV4 knockdown limits the progression of HCC. This effect is mediated by the reduction of tumor cell proliferation and migration, which may occur, at least in part, through the modulation of the ERK/ETV4/MMPs axis.

Accumulated Fe2+ drove robust ROS production via the Fenton reaction, exacerbated lipid peroxidation, upregulated ACSL4, and downregulated SCD1 and GPX4, collectively inducing ferroptosis, a form of regulated cell death specifically rescued by ferrostatin-1 or deferoxamine but not by Z-VAD-FMK or necrostatin-1, with minimal caspase activation. Notably, NCOA4 silencing substantially attenuated HUA's efficacy in overcoming SOR resistance. These findings highlight the role of HUA extract in promoting NCOA4-dependent ferritinophagy and modulating iron and lipid metabolism to enhance ferroptotic sensitivity, providing a rationale for the clinical development of HUA + SOR combination therapy in HCC.

This review explores recent mechanisms by which aberrant nuclear β-catenin accumulation fosters resistance to frontline tyrosine kinase inhibitors like sorafenib and lenvatinib through ferroptosis evasion, cancer stemness, and β-catenin stabilization. Recent preclinical studies show that combining Wnt inhibitors with immunotherapy or tyrosine kinase inhibitors can reprogram the tumor microenvironment, restore ferroptosis sensitivity, eradicate cancer stem cells, enhance CD8+ T-cell infiltration, boost anti-tumor immunity, and overcome resistance with minimal side effects. Targeting the Wnt/β-catenin pathway offers a promising strategy to transform HCC treatment and improve outcomes by exploiting this pathway as a key therapeutic vulnerability.

This study identified five 3DCRGs (SMC3, RAD21, FOXM1, MYBL2 and MTA3) that significantly influence postoperative recurrence in early-stage LUAD, Sorafenib treatment response in advanced tumors, and clinical staging. These genes are enriched in TPCs and may promote tumor evolution and therapeutic resistance by coordinating stemness maintenance and metabolic-immune crosstalk. Our findings highlight the significance of chromatin 3D architecture in LUAD and provide a theoretical foundation for its application in cancer precision medicine and therapeutic intervention.

Initial in vitro validation in a single RAIR-high/ATC-like thyroid cancer model provided proof-of-concept support for these predictions, with sorafenib showing dose-dependent cytotoxicity and suppression of RAF-MAPK signalling. A module-based RAIR signature captures a disease-focused component of a broader RAIR-ATC axis, transfers to cell-line models and can be embedded into an interpretable multimodal framework for drug-response prediction and targeted drug-class prioritisation, prioritising VEGFR/KDR and RAF/BRAF inhibitor classes as candidates for further translational evaluation in RAIR-like thyroid models.

Beta-glucan exhibits dose-dependent protective effects in a preclinical model of NASH-associated HCC, potentially mediated through antioxidant and growth factor-modulating mechanism. These findings warrant further molecular and clinical investigation.