CD36 Inhibits Triple-Negative Breast Cancer Progression by Transcriptionally Upregulating Caveolin-1 and Promoting Lipid-Reactive Oxygen Species-Related Ferroptosis

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor prognosis. Cluster of differentiation 36 (CD36), a fatty acid transporter, plays controversial roles in tumor progression. Here, we report a tumor-suppressive function of CD36 in TNBC. Analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases, along with validation in clinical samples, revealed that CD36 expression was significantly downregulated in TNBC tissues, and its low expression correlated with advanced disease stage and poorer patient prognosis. Functional assays demonstrated that CD36 knockout promoted, whereas its overexpression inhibited, the proliferation, migration, and invasion of TNBC cells. Integrated transcriptomic and proteomic analyses linked CD36 to ferroptosis, an iron-dependent form of regulated cell death. Mechanistically, CD36 enhanced the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ), which in turn upregulated the expression of caveolin-1 (CAV1). This CD36/PPARγ/CAV1 axis increased intracellular lipid peroxidation, thereby promoting ferroptosis. In vivo, a CD36 agonist suppressed, while a ferroptosis activator inhibited the metastasis of CD36-knockdown TNBC cells. Our findings identify CD36 as a novel tumor suppressor in TNBC that acts by promoting ferroptosis, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Keywords

caveolin-1 / CD36 / ferroptosis / lipid-reactive oxygen / triple-negative breast cancer

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