Abstract
<title>Abstract</title> <p>Platinum-based agents are the mainstay for triple-negative breast cancer (TNBC), but carboplatin resistance remains a critical unmet clinical challenge. Notably, we found TNBC can develop carboplatin resistance even without ERCC1-related DNA repair abnormalities, indicating a novel resistance mechanism. Using a carboplatin-resistant cell model, this study focused on PRMT5 and uncovered a pathway involving N6-methyladenosine (m6A) methylation and ferroptosis suppression: upregulated m6A “writers” METTL3/METTL14 interate with PRMT5 and mediate m6A modification of PRMT5 mRNA, which is translated via m6A “reader” YTHDF1. Then PRMT5 interacts with GPX4, stabilizing GPX4 to block ubiquitin-dependent degradation, thereby inhibiting ferroptosis and driving carboplatin resistance. Clinical data and organoid assays confirmed that sacituzumab govitecan, a Trop-2-targeting ADC, downregulates METTL3/METTL14/YTHDF1, inhibits PRMT5 mRNA m6A methylation, restores ferroptosis sensitivity, and prolongs survival in carboplatin-resistant patient. Collectively, our findings provide compelling evidence that the METTL3/METTL14/YTHDF1/PRMT5/GPX4 axis is a key therapeutic target, offering a promising sacituzumab govitecan-based strategy for carboplatin-resistant TNBC with significant clinical translational value.</p>