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Updated: May 12, 2025

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
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Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in

Yuanhang Yu1,2, Jin Hu3, Wenwen Wang4

  • 1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Science Advances
|May 9, 2025
PubMed

Insights

The deubiquitinating enzyme PSMD14 promotes triple-negative breast cancer (TNBC) growth and metastasis by stabilizing SF3B4. PSMD14 inhibition combined with arachidonic acid shows therapeutic potential for TNBC.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Deubiquitination dysregulation is critical for cancer progression.
  • The specific role of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in triple-negative breast cancer (TNBC) is largely unknown.

Purpose of the Study:

  • To investigate the function of PSMD14 in TNBC progression.
  • To elucidate the underlying molecular mechanisms.
  • To explore potential therapeutic strategies targeting PSMD14.

Main Methods:

  • Gain- and loss-of-function experiments in TNBC cells (in vitro and in vivo).
  • Mechanistic studies involving ubiquitination, protein stabilization, mRNA processing, and signaling pathways (Akt/mTOR).
  • Validation in TNBC organoid (PDO) and patient-derived xenograft (PDX) mouse models.

Main Results:

  • PSMD14 silencing inhibited TNBC cell growth, invasion, and metastasis.
  • PSMD14 de-ubiquitinates and stabilizes SF3B4.
  • SF3B4/HNRNPC complex promotes FADS1 mRNA exon inclusion, upregulating FADS1 and activating Akt/mTOR signaling.
  • PSMD14 knockdown plus arachidonic acid induced synthetic lethality in TNBC models.

Conclusions:

  • PSMD14 acts as an oncogene in TNBC progression.
  • PSMD14 influences TNBC via the SF3B4/FADS1/Akt/mTOR axis.
  • PSMD14 is a potential biomarker and therapeutic target for TNBC, with combined PSMD14 inhibition and arachidonic acid showing promise.

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