Work

Allosteric modulation of YTHDFs by ellagic acid suppresses triple-negative breast cancer via non-canonical activation of the HIF-1α pathway

Year: 2026

Type: article

Abstract: Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and YTHDF proteins are frequently overexpressed in this malignancy, which correlates with adverse prognosis. Through high-throughput drug screening, we identify ellagic acid (EA) as a compound that binds to YTHDF proteins and disrupts their interaction with N 6-methyladenosine (m 6 A)-modified RNAs. Structural and biochemical analyses show that EA targets a conserved, histidine-dependent allosteric site shared among YTHDF paralogs. This interaction induces conformational changes that disrupt m 6 A recognition and impair RNA binding, effectively inhibiting all three YTHDF proteins without compensatory escape. Phenotypically, EA suppresses TNBC cell proliferation and migration in vitro and in vivo . Mechanistically, EA enhances global mRNA stability, while selectively suppressing translation. In TNBC, EA-induced YTHDF2 inhibition stabilizes PFKFB4 mRNA, thereby increasing PFKFB4 protein, which blocks ubiquitin-dependent degradation of HIF-1α, resulting in BNIP3 induction and ultimately triggering apoptosis and necrosis. Collectively, our work unveils EA as a natural YTHDF inhibitor with compelling therapeutic potential for TNBC.

Source: Cell Reports Medicine

DOI: 10.1016/j.xcrm.2026.103045