MLN4924, a potent NAE inhibitor, has emerged as a promising anti-cancer agent based on neddylation interference...This understanding indicates that targeting neddylation could potentially be combined with immunotherapies for more effective treatment strategies. Here, we briefly outline how neddylation is organized and its modulatory roles in both tumor cells and intertumoral immune cells, proposing an optimistic outlook for neddylation-targeted therapy.

P1/2, N=53, Active, not recruiting, University of Southern California | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Jun 2026 --> Dec 2026

Neddylation inhibitors MLN4924 (Pevonedistat) and HA-9104 reduced UBE2F activity and selectively inhibited growth of Sdhb-deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability to be studied in SDH-deficient PPGL.

Moreover, we have confirmed through in vivo and in vitro experiments that MLN4924 can enhance the sensitivity to Sorafenib. Additionally, we found that patients in the high NRS group have poor prognoses and are prone to developing resistance to treatments such as Sorafenib and Oxaliplatin, while being more sensitive to 5-Fluorouracil and immunotherapy...In conclusion, this study reveals that Neddylation-related characteristics can effectively predict the prognosis and immunotherapy outcomes of HCC. Furthermore, targeting PSMD1 may represent a potential therapeutic approach for HCC.

Moreover, pharmacological inhibition of the CRL4AMBRA1 complex with MLN4924, an FDA-approved antitumor drug that blocks NEDD8-dependent Cullin-RING ligase activation, stabilizes PR and markedly restores MPA sensitivity in MPA-resistant EC cell lines and patient-derived organoid models. Collectively, these findings suggest that the CRL4AMBRA1 ubiquitin ligase facilitates PR degradation, inducing resistance to MPA. Furthermore, this study identified the CRL4AMBRA1 complex as a potential therapeutic target for overcoming MPA resistance in EC.

CCK-8 assays were performed to evaluate the effects of EXOSC4 overexpression, MLN4924, erastin and Ferrostatin-1 on AML cell viability...EXOSC4 was identified as a candidate regulatory molecule that may connect neddylation activity with ferroptosis-related cellular responses. These findings provide new insights into the molecular mechanisms of AML and support further investigation of EXOSC4 as a potential therapeutic target.

URM1 serves a protective role against oxidative stress. Pevonedistat, a potent NAE1 inhibitor that blocks protein urmylation in human cells, exhibits strong synergy with cisplatin, an agent known to induce oxidative stress, in killing liver cancer cells effectively.

We propose that low UBA3 expression may serve as a NAEi sensitivity biomarker, particularly given that MLN4924 (NAEi) phase 3 failures may be due to a lack of patient stratification. Therefore, our key findings, on the criticality of UBA3 in NAEi sensitivity, underpin future clinical evaluations.

P1, N=12, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | N=30 --> 12

Given the complex and dynamic role of STAT3 in MASLD progression, we further found that combining MLN4924 with a specific STAT3 inhibitor synergistically blocked fatty acid uptake and modulated lipid homeostasis. Overall, our findings uncover a novel regulatory network involving neddylation dysregulation during MASLD progression and highlight the combination of neddylation and STAT3 inhibition as a promising therapeutic strategy.

P2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

Co-targeting neddylation and glutamine transporter SLC1A5 synergistically exerts anti-leukemic effects, at least in part through disruption of the TCA cycle. This combination represents a novel and effective therapeutic strategy against AML.