RAS or MEK inhibition co-targeting is effective against this resistance mechanism. This study provides preclinical rationale for clinical testing of exarafenib in BRAF Class II/III cancers and unveils RAS-mediated ARAF-KSR1 complex formation as a resistance mechanism and rational co-therapy strategies.

In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.

Treatment included surgery and systemic therapies (nivolumab and ipilimumab, followed later by tovorafenib). The patient's clinical course was marked by aggressive local progression and therapeutic challenges. This case highlights the rarity of such presentations and the need for further research into the clinicopathological and molecular features of infantile melanoma arising in congenital melanocytic nevus (CMN).

We concluded for the first time that the combination of SOR and ASH-AE generates antagonistic antitumor effect in HepG2 cells. Moreover, ASH-AE can inhibit proliferation of HepG2 cells and mitigate sorafenib-induced resistance-associated markers in HepG2 cells by targeting CD90+ cells via Hedgehog pathway modulation.

With respect to drug response, PRKD1-high HCC cases exhibited increased predicted sensitivity to multiple tyrosine kinase inhibitors (TKIs), while in vitro PRKD1 knockdown reduced sorafenib sensitivity, and sorafenib treatment suppressed both PRKD1 and p-ERK1/2 levels. Collectively, our findings identify PRKD1 as a multifaceted contributor to HCC progression, immune microenvironment modulation, and TKI responsiveness. These results highlight PRKD1 as a promising therapeutic target warranting further mechanistic and translational investigation.

Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure-activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.

P1, N=65, Active, not recruiting, Genentech, Inc. | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Jun 2027

Several compounds, particularly 6f and 6h-j, demonstrated potent cytotoxicity, with IC50 values as low as 4.82-10.23 µM against MCF-7 cells, surpassing reference drugs like sorafenib and doxorubicin. In silico studies indicated strong binding interactions of the compounds with kinases, and pharmacokinetic assessments revealed favorable properties. These findings underscore the potential of benzimidazole-hydrazone derivatives as effective cancer therapeutics, meriting further investigation into their mechanisms and clinical implications.

Conventional systemic therapies such as sorafenib and its successors provide only modest survival benefits and are frequently complicated by toxicity and drug resistance...Furthermore, interactions between exosomes and gut microbiota in modulating hepatic immunity represent an emerging frontier with unexplored therapeutic implications. Continued advances in bioengineering, nanotechnology, and systems biology are expected to refine exosome-based therapies, offering novel, personalized strategies to improve outcomes for HCC patients.

Diff-Metabolic cells retained liver-specific functions with favorable prognosis, whereas the other three programs correlated with disease advancement; notably, all four states exhibited differential therapeutic vulnerabilities, including sorafenib resistance...Geneformer-based virtual knockout screening identified HSP90B1 as a convergent dependency, validated by its cancer cell essentiality, HCC overexpression, abundance in treatment-resistant tumors, and association with adverse survival. This integrated atlas establishes a framework for targeting tumor-intrinsic states and microenvironmental dependencies in HCC.

Strikingly, subtherapeutic doses of rottlerin enhanced the efficacy of clinical ferroptosis inducers (RSL3 and sorafenib), and this chemosensitization effect persisted in PKCδ-depleted models, indicating a target-agnostic mechanism. Our work provides the first demonstration of rottlerin's ferroptotic activity in HCC, positioning it as a dual degrader capable of overcoming compensatory antioxidant adaptations. These findings advocate for rottlerin's clinical development either as monotherapy or in rational combinations to augment ferroptosis-targeted HCC treatment.