2. Academic Validation
  3. Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR-MYC

Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR-MYC

  • Biochem Pharmacol. 2026 May:247:117761. doi: 10.1016/j.bcp.2026.117761.
Ao Guo 1,  Bijun Yang 2,  Aolin Xiao Huang 3,  Jie Ni 4,  Yanhui Zhang 4,  Qinlin Jiang 5,  Yunwen Yan 6,  Qichao Luo 7,  Jing Yang 8,  Bin Yuan 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui, PR China; Experimental Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei 230032 Anhui, PR China.
  • 2 Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui, PR China; The First Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601 Anhui, PR China.
  • 3 Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui, PR China; The Third Department of Thoracic Surgery, Anhui Chest Hospital, Hefei 230022 Anhui, PR China.
  • 4 Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui, PR China.
  • 5 Hefei No.45 Middle School, Hefei 230000 Anhui, PR China.
  • 6 Department of Breast Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022 Anhui, PR China.
  • 7 Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui, PR China. Electronic address: [email protected].
  • 8 Experimental Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei 230032 Anhui, PR China. Electronic address: [email protected].
  • 9 Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui, PR China; The First Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601 Anhui, PR China; The Third Department of Thoracic Surgery, Anhui Chest Hospital, Hefei 230022 Anhui, PR China. Electronic address: [email protected].
PMID: 41621692 DOI: 10.1016/j.bcp.2026.117761
Abstract

Glutamine metabolism is a key driver of tumor progression, yet the molecular basis and prognostic relevance of glutamine metabolism-related genes in breast Cancer (BC) remain incompletely defined. In this study, integrated analysis of public datasets identified Actin-like protein 8 (ACTL8) as a key prognostic gene significantly upregulated in BC tissue and associated with poor patient survival. In vitro, shRNA knockdown of ACTL8 reduced MYC expression and its downstream targets SLC1A5 and GLS1, suppressing cell proliferation, migration and invasion. This disruption led to impaired redox homeostasis as evidenced by reduced GSH/GSSG and NADPH/NADP+ ratios. Mechanistically, MYC overexpression restored metabolic Enzymes and phenotypes but failed to rescue p-AKT levels, confirming ACTL8 acts upstream of the PI3K/Akt/mTOR axis. Virtual screening identified Momordin Ic as a small molecule that directly interacts with ACTL8. Surface plasmon resonance (SPR) and Thermal shift assay (TSA) confirmed this high-affinity binding, which destabilized ACTL8 and promoted its ubiquitin-proteasome degradation. Moreover, ACTL8 knockdown significantly attenuated the sensitivity of BC cells to Momordin Ic treatment, confirming ACTL8 as the specific therapeutic target. In vivo, suppression of ACTL8 markedly reduced tumor growth. Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.

Keywords

ACTL8; Breast cancer; CB-839; Glutamine metabolism; Momordin ic; Therapeutic target.

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