What does this research mean for the field?

The small molecule GL-V9 suppresses colorectal cancer independently of p53 status by acting as a molecular glue that promotes the binding of cytosolic MDM2 with NDUFS1, which disrupts mitochondrial homeostasis and induces integrated stress response-triggered apoptosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

What question did this study set out to answer?

To elucidate the mechanism through which GL-V9 modulates MDM2 and NDUFS1 to disrupt mitochondrial homeostasis and trigger apoptosis in colorectal cancer.

April 10, 2026Open Access

GL-V9 disrupts the mitochondrial homeostasis and triggers the integrated stress response by promoting the binding of cytosolic MDM2 with NDUFS1 in colorectal cancer

Key Points

To elucidate the mechanism through which GL-V9 modulates MDM2 and NDUFS1 to disrupt mitochondrial homeostasis and trigger apoptosis in colorectal cancer.
Analyzed binding interactions between MDM2 and NDUFS1 using pull-down assays and immunofluorescence.
Conducted molecular docking and cellular thermal shift assays to study GL-V9's binding to MDM2.
Evaluated mitochondrial homeostasis through assessments of mitochondrial membrane potential and ATP generation.
Monitored the activation of the OMA1-DELE1 axis via signaling assays for apoptosis.
GL-V9 promotes MDM2's binding with NDUFS1, leading to mitochondrial dysfunction.
Induction of the integrated stress response results in apoptosis, independent of p53.
Activation of the OMA1-DELE1 signaling pathway contributes to stress-induced cell death.
GL-V9 provides a novel approach for CRC treatment with a favorable safety profile.

Abstract

• MDM2 plays a non-oncogenic potential in CRC by restricting mitochondrion localization of NDUFS1. • GL-V9 is a new MDM2 modulator and suppresses CRC independent of p53 status • GL-V9 facilitates the binding of MDM2 with NDUFS1, and disrupts the mitochondrial homeostasis. • Mitochondrial stress activates OMA1-DELE1 axis and induces ISR-triggered apoptosis. The oncogenic role of mouse double minute 2 (MDM2) is primarily attributed to its regulation of p53-dependent signaling cascades. The colorectal cancer (CRC) remains in the top five most prevalent and lethal cancers. P53 mutations are detected in 45–50% of CRC, leading to the failure of such MDM2 inhibitors in clinical trials. Small molecular compound GL-V9 targets MDM2 and leads a non-canonical function of MDM2 mediated anti-CRC effects. Interaction of MDM2 with NDUFS1 as well as the mitochondrial location of NDUFS1 were assessed by a pull-down assay and immunofluorescence analysis. The binding of GL-V9 to MDM2, was analyzed by molecular docking, cellular thermal shift assay (CESTA), surface plasmon resonance (SPR), GST-pulldown and amino acid mutations. Mitochondrial homeostasis was evaluated by mitochondrial membrane potential, mitochondrial superoxide, ATP generation and oxygen consumption rate. Different from MDM2 inhibitors, GL-V9 binds to the MDM2 amino-terminal domain (amino acids 1–101) and facilitates the interaction of MDM2 with NDUFS1 in cytoplasm through a p53-independent manner, instead of disruption of p53-MDM2 binding or the promotion of MDM2 protein degradation. This process additionally inhibits the formation of electron transport chain complex I and disrupts the mitochondrial homeostasis, which finally activates OMA1-DELE1 signaling axis and induces the integrated stress response (ISR)-triggered apoptosis. This study provides a novel candidate for CRC therapy with favorable safety profile. Importantly, the novelty mode of action by GL-V9, working as molecular glue for MDM2/NDUFS1, provides a new insight for targeting MDM2 regardless of p53 status.

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Cite This Study

Zhang et al. (Wed,) studied this question.

synapsesocial.com/papers/69d894ad6c1944d70ce058fb https://doi.org/https://doi.org/10.1016/j.jare.2026.04.019

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