Lee, Bok-Soon Park, Yea-In Liu, Hengtian Kim, Sang Gyu Kim, Hyo Jeong Choi, Ji-Hye Rho, Si Hyun Padilla, Joselyn Roh, Jin Woo, Hyun Goo Seo, Hae Jin Choi, Man Ho Jeong, Yu-Jin Lien, Evan C. Mehdi, Syed Hassan Lee, Dongjoon Yoon, Donghoon Kim, Chul-Ho Lee, Jiyoung 2025-06-25T08:30:05Z 2025-06-25T08:30:05Z 2025-06-23 2025-09 0304-3835 https://pubs.kist.re.kr/handle/201004/152692 Alterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability. English Elsevier BV The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma Article 10.1016/j.canlet.2025.217842 1 Cancer Letters, v.628 Cancer Letters 628 N scie scopus 001506756200001 Oncology Oncology Article CHOLESTEROL-METABOLISM CANCER OXYSTEROLS RISK MS Cholesterol metabolism DHCR7 DHCR24 7-Dehydrocholesterol Head and neck cancer ER stress