Abstract 6661: Effect of berberine on cholesterol regulation in pancreatic ductal adenocarcinoma via heat shock factor 1

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by poor prognosis and elevated metabolic activity, including dysregulated lipid metabolism that supports aggressive growth. Cholesterol homeostasis, involving synthesis, uptake, and efflux, is pivotal for tumor progression. The pro-oncogenic transcription factor heat shock factor 1 (HSF1) has been reported to sustain the increasing metabolic demands of cancer cells by directly inhibiting AMP-activated protein kinase (AMPK), leading to an enhanced de novo cholesterol synthesis process and lipogenic phenotype in human melanoma cells. Berberine, a natural alkaloid with anti-cancer properties, has demonstrated efficacy in modulating cholesterol metabolism. However, its role in cholesterol regulation through HSF1 in PDAC remains poorly understood. Objectives: To investigate the role of berberine in modulating cholesterol homeostasis in PDAC through the regulation of HSF1. Methods: Multiple human pancreatic epithelial cells and cancer cell lines were treated with berberine to evaluate its effects on cholesterol regulation. Immunoblotting was used to assess changes in key proteins associated with cholesterol metabolism, focusing on determining berberine's impact on cholesterol efflux pathways. Results: Berberine treatment significantly reduced total HSF1 levels, phosphorylation at Serine326, and downstream target HSP72 in a dose-dependent manner. Berberine treatment also increased AMPK phosphorylation at Thr172 and decreased cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1). However, the expression of another cholesterol efflux transporter, ABCG2, remained unaffected by berberine treatment. Conclusion: This study reveals a novel mechanism by which berberine exerts an anti-cancer effect in PDAC by modulating cholesterol regulation through HSF1. Citation Format: Ahmad Hegazi, Rejina Shrestha, Shruti Ghai, Kuo-Hui Su. Effect of berberine on cholesterol regulation in pancreatic ductal adenocarcinoma via heat shock factor 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6661.