Baicalein suppresses mitochondrial biogenesis via the RBM43/PGC-1α axis in triple-negative breast cancer cells

Mitochondrial biogenesis, a crucial process driven by the master regulator PGC-1α, is frequently upregulated in Triple-Negative Breast Cancer (TNBC), contributing to enhanced metabolic adaptability and poor prognosis. The natural flavonoid Baicalein has demonstrated promising anti-cancer properties. This study investigates the effect and underlying mechanism of Baicalein on mitochondrial biogenesis in TNBC cells. Our results show that Baicalein significantly inhibits cell viability and induces cytotoxicity in MDA-MB-231 cells. Mechanistically, Baicalein impairs mitochondrial function, reduces mitochondrial mass and DNA content, and suppresses the expression of key biogenesis factors, including TFAM. Notably, Baicalein potently decreases PGC-1α protein levels without affecting its mRNA, suggesting post-transcriptional regulation. We further identify that Baicalein upregulates the RNA-binding protein RBM43. Crucially, silencing RBM43 significantly attenuates Baicalein's inhibitory effects on PGC-1α protein expression, mitochondrial DNA content, and ATP production. These results were confirmed in a second TNBC cell line, HCC1937. RNA immunoprecipitation assays demonstrated that RBM43 physically associates with PGC-1α mRNA, and that this association is enhanced by Baicalein. Furthermore, Baicalein selectively affected TNBC cells compared to normal mammary epithelial MCF-10A cells, with minimal induction of RBM43 or suppression of PGC-1α in the non-tumorigenic line. In conclusion, our findings reveal that Baicalein suppresses mitochondrial biogenesis in TNBC by upregulating RBM43 to inhibit PGC-1α expression, highlighting its potential as a therapeutic agent against TNBC.