Abstract Triple-negative breast cancer (TNBC) frequently acquires chemoresistance, leading to poor clinical outcomes. Phospholipid scramblase 1 (PLSCR1) has been implicated in breast cancer progression, yet its precise role and underlying mechanisms in TNBC chemoresistance remain elusive. Here, we demonstrate that PLSCR1 is significantly upregulated in chemoresistant TNBC cell lines and patient samples. Mechanistically, PLSCR1 interacts with EGFR, promoting its phosphorylation and subsequent activation of the MAPK signaling pathway, which in turn upregulates the efflux pumps P-gp and MRP1. Concurrently, PLSCR1 mRNA undergoes METTL3-mediated m6A modification, which is recognized by the m6A reader IGF2BP3, leading to enhanced mRNA stability and translational efficiency. Functional studies revealed that PLSCR1 knockdown resensitizes resistant cells to epirubicin, whereas its overexpression exacerbates resistance both in vitro and in vivo. Clinically, elevated PLSCR1 expression correlates with reduced sensitivity to neoadjuvant chemotherapy and poorer prognosis in TNBC patients. Notably, Mogroside IV-A, a specific PLSCR1 inhibitor, effectively overcomes chemoresistance by disrupting PLSCR1-mediated EGFR activation. Collectively, our findings establish PLSCR1 as a critical node integrating the METTL3/IGF2BP3 epigenetic axis with EGFR-MAPK signaling to drive TNBC chemoresistance, and highlight PLSCR1 as a promising therapeutic target for combating drug resistance in TNBC.
Lu et al. (2026) studied this question.