NAMPT (Nicotinamide Phosphoribosyltransferase)

The optimized degrader, U42, exhibited low nanomolar antiproliferative activity, robust intracellular and extracellular NAMPT degradation, excellent metabolic stability, favorable pharmacokinetics, and sustained efficacy in mammosphere models, three-dimensional breast cancer cultures not previously explored with NAMPT degraders. These findings highlight U42 as a lead compound and provide strong rationale for advancing NAMPT-directed PROTACs as a therapeutic strategy in breast cancer.

In vivo, A9 showed significant antitumor efficacy in SH-SY5Y xenograft model. Collectively, these findings establish A9 as a promising therapeutic approach for neuroblastoma, combing the metabolic vulnerability of NAMPT inhibition with the tumor selectivity of GD2-directed delivery to achieve potent and targeted antitumor activity.

Furthermore, NAD+ depletion and JEV production increased when salvage biosynthesis was restrained through NAMPT knockdown, but these effects were reversed by supplementing nicotinamide riboside (NR) in NAMPT knockdown T98G cells...In conclusion, this study demonstrates that JEV infection disrupts NAD+ metabolism, and restoring NAD+ levels inhibits JE progression. Therefore, maintaining NAD+ homeostasis and regulating its metabolic pathway could be a promising therapeutic approach for JE.

Further studies revealed that this therapeutic effect was achieved by inhibiting the NAD+ level, as well as the protein expression of NAMPT, PARP1, and inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, and P65. In conclusion, FK866 exhibits therapeutic potential for the treatment of liver fibrosis.

Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation...These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers.

Notably, nicotinic acid coadministration enhanced tolerability without compromising antitumor activity in vivo. Collectively, these findings identify N16 as a promising NAMPT inhibitor with translational potential for treating metabolically vulnerable gastric cancer, particularly NAPRT-deficient subtypes.

While CDKN2A loss is classically associated with cell cycle deregulation through the p16-Cdk4-Rb axis, our findings suggest an additional layer of metabolic vulnerability arising from altered NAD homeostasis in CDKN2A -deleted glioblastoma, revealing a previously unrecognized metabolic-genetic interface for rationally revisiting NAD + targeting strategies, moving beyond the broad inhibition approaches.

In three-dimensional (3D) spheroids, compound 45 reduced the cumulative spheroid area approximately 10-fold more than the single-target inhibitors FK866 or SLC-0111 and induced apoptosis through NAD depletion, mitochondrial dysfunction, and suppression of ERK/mTOR signaling. These results support dual hCA IX/XII-NAMPT inhibition as an effective strategy to impair tumor growth and survival under hypoxic stress.

Moreover, 10n·HCl provoked immunogenic cell death (ICD) and activated the cGAS-STING pathway, thereby stimulating antitumor immunity. These results establish 10n as a promising lead compound for the development of dual PARP/NAMPT inhibitors to treat BRCA wild-type TNBC.

Our findings suggest that the TyG index reflects not only insulin resistance and atherogenic dyslipidemia, but also low-grade inflammation and adipokine imbalance in patients with MetS. Due to its simplicity and cost-effectiveness, the TyG index could be a useful tool for early metabolic risk assessment and identifying adipose tissue dysfunction.

Finally, this paper envisions the broad prospects of bariatric metabolic surgery in future adjuvant breast cancer treatment. By comprehensively employing lifestyle interventions, drug therapies, and bariatric metabolic surgery, we can provide patients with more comprehensive and personalized treatment plans to achieve better therapeutic outcomes and prognosis.

P=N/A, N=200, Not yet recruiting, Wangjing Hospital, China Academy of Chinese Medical Sciences