ECE2, NFE2L3, PFKFB3, FADS2, and SEPT3 are associated with pyrimidine metabolism in TNBC. A risk model and nomogram were successfully constructed based on these genes, providing a theoretical basis for the treatment of TNBC patients. We confirm the model's validity in TNBC by validating SEPT3 (a key PyMRG) regulates TNBC cell proliferation, migration, and invasion.

P1/2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

Head and neck squamous cell carcinoma (HNSCC) is currently the sixth most prevalent cancer worldwide and is marked by a high tumor relapse frequency due to acquired chemoresistance, requiring alternative strategies to sensitize resistant tumor cell populations to treatment. In vivo studies confirmed that SG treatment followed by ABT-263 limited tumor progression and extended survival without notable toxicity. Thus, SG in combination with senolytic treatment may be an effective strategy for suppressing the growth of cisplatin-resistant HNSCC cells.

P1, N=17, Active, not recruiting, City of Hope Medical Center | Trial completion date: Apr 2026 --> Mar 2027 | Trial primary completion date: Apr 2026 --> Mar 2027

This study identifies eight EMT-related prognostic genes in PTC and highlights their potential value as biomarkers for prognostic evaluation and therapeutic stratification.

Overall, ABT-263 therapy partially mitigates influenza severity in aged mice, primarily through dampening acute and chronic inflammation. Most of these effects were age-dependent, suggesting a role for pre-existing senescent cells.

A first milestone was the discovery of ABT-263 (navitoclax), a dual BCL-2/BCL-xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL-2 inhibitor, marked a major breakthrough, demonstrating potent pro-apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL-2 family members remains challenging, largely due to the structural characteristics of the BH3-binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL-xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.

Background: BH3 mimetics (such as venetoclax and navitoclax) are increasingly investigated in the context of the "one-two punch" anticancer strategy, wherein senescence-inducing therapies are combined with senolytic clearance. In FAERS, venetoclax combined with senescence-inducing chemotherapy shows stronger reporting signals for leukopenia and multi-lineage cytopenias and for several serious outcome categories compared with monotherapy. These reporting patterns highlight the need for further care in terms of clinical implementation of the currently investigated senolytics prior to the consideration of the "one-two punch" strategy.

Early "first-generation" senolytics, including navitoclax (ABT-263) and the dasatinib-quercetin (D + Q) combination, provided proof-of-concept that selective removal of SnCs can alleviate certain fibrotic, metabolic, and cardiovascular pathologies in preclinical studies. These approaches offer potentially more targeted and personalized therapeutic options but face significant challenges, including immunopathology, manufacturing complexity, off-target effects, and long-term safety concerns. The ongoing shift from broad inhibition to precision reprogramming represents a promising but preliminary step in the treatment of age-related diseases.

Nine inhibitors (i.e., venetoclax, navitoclax; and seven previously prioritized BCL-2 hit inhibitors by our research group) are profiled across solvent systems, including neat DMSO, 10% DMSO, and a ternary matrix (S3: 10% DMSO, 90% sulfobutylether-β-cyclodextrin (SBE-β-CD) in saline). Comparisons with time-resolved fluorescence energy transfer (TR-FRET) analysis, in vitro assays, and MM/GBSA binding free energy results confirmed DSC's accuracy in detecting binding energetics. Collectively, these results position DSC as a robust, material-efficient tool for thermodynamic screening of BCL-2 ligands and other poorly soluble compounds, and as a practical complement to isothermal titration calorimetry when solubility or kinetic limitations prevail.

Venetoclax, navitoclax, and obatoclax represented significant advances in apoptosis-targeted therapy, with venetoclax emerging as the most clinically successful agent. However, resistance mechanisms and side effects were significant challenges, necessitating further preclinical and clinical studies to optimize the therapeutic potential of these agents.

Drug sensitivity prediction indicated that high-risk patients may respond better to agents such as Tozasertib and Navitoclax. This study establishes a robust, demethylation-driven six-gene signature that effectively stratifies HCC patients into distinct prognostic groups. The model integrates multi-omic insights into tumor biology and therapeutic vulnerability, providing a clinically actionable framework for personalized risk assessment and treatment planning in hepatocellular carcinoma.