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

  • J Adv Res. 2026 Apr 7:S2090-1232(26)00302-4. doi: 10.1016/j.jare.2026.04.019.
Yibo Zhang  1 ,  Chen Xun  2 ,  Chenxiao Shi  1 ,  Rui Wang  1 ,  Yuan Gao  3 ,  Di Pan  4 ,  Yongjian Guo  5 ,  Libin Wei  6
Affiliations
  • 1. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing 210009, China.
  • 2. Nanjing Tianyinshan Hospital of China Pharmaceutical University, #3789 Jiyin Rd, Nanjing 211112, China.
  • 3. Public Laboratory Platform, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing 210009, China.
  • 4. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine / High Application of Natural Medicinal Resources Engineering Center of Guizhou Province (Key Laboratory of Novel Anti-Cancer Drug Targets Discovery and Application), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China. Electronic address: [email protected].
  • 5. School of Biopharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing 211198, China. Electronic address: [email protected].
  • 6. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing 210009, China. Electronic address: [email protected].
PMID: 41951044 DOI: 10.1016/j.jare.2026.04.019
Abstract

Introduction: 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.

Objectives: Small molecular compound GL-V9 targets MDM2 and leads a non-canonical function of MDM2 mediated anti-CRC effects.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
Colorectal cancer; GL-V9; Integrated stress response; MDM2-NDUFS1 interaction; Mitochondrial homeostasis.
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