HSPA6 Promotes Ferroptosis in Triple-Negative Breast Cancer by Rewiring Lipid Metabolism to Potentiate Membrane Lipid Peroxidation

Given the lack of effective targeted therapeutic options for triple-negative breast cancer (TNBC), there is an imperative demand for innovative treatment approaches, with ferroptosis standing out as a promising direction. This study identifies HSPA6 as a key ferroptosis sensitizer in TNBC. Mechanistically, HSPA6 binds to NF-κB p65, inhibits its nuclear translocation and Ser468 phosphorylation, thereby suppressing transcription of the lipogenic enzyme FASN and downregulating phospholipid-remodeling enzymes LPCAT1/cPLA2. This dual inhibition enriches membrane phospholipids with polyunsaturated fatty acids, heightening peroxidation susceptibility and triggering ferroptosis. Concurrently, HSPA6-mediated suppression of lipogenesis depletes palmitate, thereby attenuating ANKIB1 palmitoylation and inhibiting its E3 ligase activity. This impairs K48-linked ubiquitination and degradation of HSPA6, forming a stabilizing positive feedback loop. Our study uncovers a HSPA6-p65-FASN-ANKIB1 axis linking lipid metabolism to ferroptosis, offering a novel TNBC therapeutic target.