Abstract Introduction: Lipid metabolism disorders are closely linked to pancreatic cancer progression, with intricate interactions underlying this association. Small nucleolar RNA host gene 14 (SNHG14), a long non-coding RNA with oncogenic properties, has been implicated in the progression of various malignant tumors including pancreatic cancer. However, its specific contribution to tumor lipid metabolism, particularly in pancreatic cancer, remains unclear. Methods: Pancreatic cancer models with SNHG14 overexpression or knockdown were established to assess its effects in vitro. Quantitative RT-PCR and Western blotting evaluated SNHG14's influence on the downstream target USP20, while cholesterol detection assays examined its role in regulating intracellular cholesterol. In vivo, a nude mouse subcutaneous xenograft model was used to study tumor growth following SNHG14-knockdown cell injection, confirming its role in pancreatic cancer progression. Tumor tissues were analyzed for USP20 expression and cholesterol content, further supporting SNHG14’s regulatory function. Molecular mechanisms were explored via dual luciferase reporter assays and RIP, confirming the interaction between SNHG14 and miR-105-5p, and its regulation of USP20 mRNA stability through the ceRNA pathway. Co-IP revealed the USP20-HMGCR interaction, while ChIP identified IRF1’s binding to SNHG14, elucidating its nuclear regulatory pattern. Results: SNHG14 significantly upregulated USP20 mRNA and protein expression, consistent with its effects in vitro and in vivo. SNHG14 overexpression promoted pancreatic cancer cell proliferation, invasion, and xenograft growth, while SNHG14 knockdown inhibited these effects, confirming SNHG14’s oncogenic role via USP20 upregulation. In vivo, SNHG14 knockdown reduced cholesterol levels in pancreatic tumors, identifying SNHG14 as a key regulator of cholesterol metabolism linked to cholesterol accumulation in pancreatic cancer. In the cytoplasm, SNHG14 acts as a molecular sponge for miR-105-5p, competing with it to regulate USP20 mRNA stability and enhance USP20 expression. As a deubiquitinating enzyme, USP20 promotes HMGCR stability and activates the cholesterol synthesis pathway. In the nucleus, IRF1 binds to the SNHG14 promoter, facilitating its transcription. SNHG14 amplifies HMGCR expression via the miR-105-5p/USP20 axis, remodeling cholesterol metabolism and accelerating disease progression. Citation Format: Zhu Ke, Dong Yan, Yingying Tong, Yurong Cheng, Chan Zhang. LncRNA SNHG14 remodels cholesterol metabolism to inhibit pancreatic ductal adenocarcinoma via recruiting USP20 and down-regulating miR-105-5p through IRF1-SNHG14-USP20-HMGCR axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7221.
Ke et al. (Fri,) studied this question.