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HSPA6 Promotes Ferroptosis in Triple-Negative Breast Cancer by Rewiring Lipid Metabolism to Potentiate Membrane Lipid
Lin-Yue Hai1,2,3,4, Zhi-Hao Yu1,2,3,4, Wen-Bo Liu1,2,3,4
1The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
Abstract:
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.
Insights
Heat shock protein A6 (HSPA6) sensitizes triple-negative breast cancer (TNBC) to ferroptosis by inhibiting lipogenesis and NF-κB signaling. This discovery reveals a novel therapeutic target for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) lacks effective targeted therapies.
- Ferroptosis presents a promising avenue for innovative cancer treatment.
Purpose of the Study:
- To identify novel therapeutic targets for TNBC.
- To investigate the role of HSPA6 in ferroptosis induction in TNBC.
Main Methods:
- Investigated HSPA6 as a ferroptosis sensitizer in TNBC.
- Elucidated the molecular mechanism involving NF-κB p65, FASN, LPCAT1, cPLA2, and ANKIB1.
- Analyzed lipid metabolism and ferroptosis induction pathways.
Main Results:
- HSPA6 acts as a key ferroptosis sensitizer in TNBC.
- HSPA6 suppresses NF-κB p65 activity, inhibiting lipogenesis (FASN) and phospholipid remodeling (LPCAT1/cPLA2).
- This leads to increased membrane phospholipid peroxidation and ferroptosis, with a positive feedback loop stabilizing HSPA6.
Conclusions:
- A novel HSPA6-p65-FASN-ANKIB1 axis linking lipid metabolism to ferroptosis in TNBC was uncovered.
- HSPA6 represents a promising therapeutic target for TNBC treatment.
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