SOAT1 exacerbates tumor progression by promoting YAP signaling activation and attenuating endoplasmic reticulum stress

Abstract Metabolic reprogramming is a hallmark of malignancy, with profound alterations in cellular metabolism driving cancer progression. However, the precise mechanisms by which these metabolic changes promote tumor growth remain poorly understood. Here we mined metabolic activity at single‐cell resolution as well as bulk‐RNA levels, and found that cholesterol biosynthesis is obviously upregulated in breast cancer, particularly triple‐negative breast cancer. We identified sterol O‐acyltransferase 1 (SOAT1) was highly expressed in triple‐negative breast cancer (TNBC) with poor progression and prognosis. Functional studies demonstrated that SOAT1 suppression—either through genetic knockdown or pharmacological inhibition—effectively curbed cancer cell proliferation and migration, induced cell cycle arrest, and significantly inhibited the in vivo growth of breast cancer xenografts. Similar effects were observed in prostate cancer models. Mechanistically, targeting SOAT1 disrupted cholesterol metabolic homeostasis, leading to inactivation of the YAP signaling pathway and induction of endoplasmic reticulum (ER) stress. Collectively, our findings highlight the critical role of SOAT1 in TNBC progression through modulation of the YAP pathway and ER stress, and propose a novel therapeutic strategy for TNBC by targeting cholesterol metabolism.