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PLSCR1 drives chemoresistance in TNBC via METTL3/IGF2BP3-mediated mRNA stabilization and EGFR-MAPK pathway activation

Yao Lu1, Xueliang Zeng2, Shixiong Peng3

  • 1School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China.

Cell Death & Disease
|May 15, 2026
PubMed

Insights

Phospholipid scramblase 1 (PLSCR1) drives chemoresistance in triple-negative breast cancer (TNBC) by activating EGFR-MAPK signaling and enhancing mRNA stability. Inhibiting PLSCR1 resensitizes tumors to chemotherapy, offering a new therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Triple-negative breast cancer (TNBC) often develops chemoresistance, leading to poor patient outcomes.
  • The role of Phospholipid scramblase 1 (PLSCR1) in TNBC chemoresistance is not well understood.

Purpose of the Study:

  • To elucidate the mechanisms by which PLSCR1 contributes to chemoresistance in TNBC.
  • To investigate PLSCR1 as a potential therapeutic target for overcoming drug resistance in TNBC.

Main Methods:

  • Analysis of PLSCR1 expression in chemoresistant TNBC cell lines and patient samples.
  • Investigating the interaction between PLSCR1, EGFR, and the MAPK pathway.
  • Assessing the role of METTL3-mediated m6A modification and IGF2BP3 in PLSCR1 mRNA stability.
  • In vitro and in vivo functional studies involving PLSCR1 knockdown and overexpression.
  • Clinical correlation analysis of PLSCR1 expression with chemotherapy sensitivity and prognosis.
  • Evaluating the efficacy of a PLSCR1 inhibitor (Mogroside IV-A).

Main Results:

  • PLSCR1 is significantly upregulated in chemoresistant TNBC.
  • PLSCR1 interacts with EGFR, activating the MAPK pathway and upregulating drug efflux pumps (P-gp, MRP1).
  • METTL3-mediated m6A modification enhances PLSCR1 mRNA stability and translation via IGF2BP3.
  • PLSCR1 knockdown resensitizes cells to epirubicin; overexpression increases resistance.
  • High PLSCR1 expression correlates with poor response to neoadjuvant chemotherapy and worse prognosis.
  • Mogroside IV-A effectively overcomes chemoresistance by inhibiting PLSCR1-mediated EGFR activation.

Conclusions:

  • PLSCR1 is a key mediator of chemoresistance in TNBC, integrating epigenetic regulation (METTL3/IGF2BP3) with signaling pathways (EGFR-MAPK).
  • Targeting PLSCR1, potentially with inhibitors like Mogroside IV-A, represents a promising therapeutic strategy for overcoming drug resistance in TNBC.

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