Ferroptosis inducers (sorafenib, erastin) heightened LDH release and reduced viability, while inhibitors (ferrostatin-1, U0126) had opposing effects...STXBP1 functions as a tumor suppressor in glioma, regulating ferroptosis and EMT. It shows potential as a therapeutic target in glioma management.

Drug sensitivity profiling revealed ST3GAL4 exhibited strong correlations with AZ628 (pan-RAF inhibitor) and RDEA119 (MEK inhibitor), which was further validated by molecular docking showing excellent binding affinities (binding energies: -8.7 and - 7.2 kcal/mol). This study provides structural evidence for targeted therapeutic strategies in ST3GAL4-overexpressing melanoma and establishes foundations for age-stratified immunotherapy.

Importantly, dual blockade of CD147+-hypo-Migs macropinocytosis and VM formation enhances the sorafenib-killing efficacy to HCC. Conclusively, our findings uncover a novel sorafenib resistance mechanism induced by CD147+-hypo-Migs, and highlight dual-targeting of macropinocytosis and VM as a promising strategy to overcome the sorafenib resistance in HCC.

Moreover, combined treatment with SID and sorafenib reduced the tumor growth in a xenograft model...Moreover, the downregulation of USP53 suppressed the expression of Survivin. Therefore, Cat L can be considered a potential candidate molecular target for the treatment of RCC.

SP1 knockdown partially reproduced several of these effects, supporting a contribution of SP1-dependent transcriptional programs to these phenotypes. Overall, these findings identify SP1-associated transcriptional networks as potential regulators of CSC features and therapeutic resistance in HCC and support targeting SP1-associated transcriptional programs as a strategy to enhance sorafenib efficacy.

Molecular docking revealed that compound BIT (hybrid in which ketone group of isatin clubbed with thiosemicarbazide) exhibited a docking score of -10.2 kcal/mol, surpassing the binding affinities of the reference ligands axitinib and sorafenib, highlighting its promising potential. The BIT compound was evaluated, and the results indicated that it exhibited significant inhibitory activity against MCF-7 cells at a concentration of 30 mM.

Several derivatives displayed significantly higher potency than sorafenib, with compound 5d emerging as the lead molecule (IC50 = 4.10 µM, SI = 12.0).To elucidate the molecular basis of activity, induced-fit docking and MM-GBSA calculations were performed against four key colorectal cancer-related targets (TNF-α, PI3K p110α, AKT1, and mTOR)...In addition, DFT, ESP, and GCR analyses revealed that 5d combines optimal electronic reactivity with stability, while ADME predictions indicated a favorable pharmacokinetic profile. Overall, 5d is identified as a promising multi-target lead for colorectal cancer therapy.

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.