Adipocyte‐Derived Palmitic Acid Promotes Breast Cancer Malignancy via <scp>ZDHHC15</scp> ‐Mediated S‐Palmitoylation of <scp>PPARγ</scp>

Peroxisome proliferator-activated receptor gamma (PPARγ), a well-characterized regulator of adipogenesis, also functions as a tumor suppressor in breast cancer. However, the PPARγ agonist rosiglitazone has shown limited clinical efficacy, highlighting the importance of understanding PPARγ regulation within the tumor microenvironment. Here, we demonstrate that adipocyte-derived palmitic acid promotes PPARγ S-palmitoylation via zinc finger DHHC-domain containing protein 15 (ZDHHC15), as confirmed by acyl-biotin exchange (ABE) assay. Immunoblot, RT-qPCR, and immunoprecipitation further revealed that this modification leads to ubiquitin-mediated proteasomal degradation of PPARγ. Functional studies using adipocyte-conditioned media and an oxygen-permeable 3D spheroid culture system showed that PPARγ palmitoylation promotes breast cancer malignancy and confers resistance to rosiglitazone. Notably, the palmitoylation inhibitor 2-bromopalmitate (2-BP) stabilizes PPARγ, suppressing breast cancer malignancy. Furthermore, 2-BP synergistically enhances the therapeutic efficacy of rosiglitazone, suggesting that targeting PPARγ S-palmitoylation represents a promising therapeutic strategy in breast cancer.