This disruption results in enhanced accumulation of protein aggregates, increased protein polyubiquitination, endoplasmic reticulum stress, and activation of apoptotic pathways. Collectively, our findings support the repurposing of ceritinib in combination with carfilzomib as a translationally relevant and safe strategy to circumvent PI resistance in MM, warranting further clinical investigation in the relapsed/refractory disease setting.

The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin's reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation.

In addition, we also found that the NF-κB pathway-related anti-AML effect of bortezomib partially relied on LSP1. This study revealed that LSP1 plays a crucial role in the progression of AML, indicating its potential as a prognostic biomarker and therapeutic target.

P1/2, N=5, Completed, University of Chicago | Recruiting --> Completed | Trial completion date: Dec 2026 --> Sep 2025 | Trial primary completion date: Sep 2026 --> Sep 2025

P2, N=32, Completed, University Hospital, Lille | Unknown status --> Completed | N=80 --> 32

These findings uncover a previously unrecognized role of TRIP13 in regulating mitochondrial integrity under proteotoxic stress, thereby contributing to BTZ resistance. Targeting TRIP13 may represent a novel therapeutic approach to improve outcomes in MM patients.

Additionally, MG132 inhibited the differentiation of endothelial progenitor cells (EPCs) into smooth muscle cells (SMCs) and reduced the levels of inflammatory cytokines, including high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). Moreover, MG132 effectively suppressed the expression of NF-κB P65 and its downstream signaling pathway, intercellular adhesion molecule-1 (ICAM-1).

This model underscores the pivotal role of TME components in shaping therapeutic outcomes and offers a scalable, clinically translatable tool for personalized risk stratification. Our findings highlight the necessity of integrating microenvironmental insights into MM prognostication and pave the way for microenvironment-informed therapeutic decision-making.

Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics.

P2, N=22, Recruiting, University of Utah | Trial primary completion date: Dec 2025 --> Dec 2026

HSP47 inhibition promotes immune evasion by upregulating CD155 via the TRAF2-NF-κB pathway, which impairs CD8+ T cell-mediated antitumor immunity. The combination of HSP47 inhibition with CD155/TIGIT blockade enhances therapeutic efficacy, suggesting a promising strategy for combination cancer therapies.

Decreased NF-κB expression seems to be an independent prognostic factor for improved renal function. The results demonstrated for the first time the in vivo protein expression of MDM2 in the bone marrow of patients with multiple myeloma, as well as the possible effect of bortezomib on the expression of this protein in the microenvironment of multiple myeloma.