SNHG15 inhibits the tricarboxylic acid cycle and promotes HCC progression by facilitating the phosphorylation of PDK1 and PDHE1α

Abstract Glucometabolic reprogramming is a defining feature of hepatocellular carcinoma (HCC). The pyruvate dehydrogenase complex (PDHc) serves as a critical intermediary between glycolysis and oxidative phosphorylation by facilitating the oxidation of pyruvate within the tricarboxylic acid cycle. However, its potential involvement in other facets of metabolic regulation has yet to be fully elucidated. Here, we found that PDHE1α could bind RNA and that lncRNA SNHG15, a small nucleolar RNA host gene, may interact with PDHE1α. Mechanistic analysis suggested that SNHG15 facilitated the interaction between PGK1 and PDK1, as well as between PDK1 and PDHE1α, resulting in increased phosphorylation of PDK1 and PDHE1α. This in turn suppressed the Tricarboxylic Acid (TCA) Cycle and promoted glycolysis in HCC cells. In xenograft models, SNHG15 promoted tumor growth with increased lactate production and elevated phosphorylation of PDK1 and PDHE1α, while DCA administration significantly reversed these oncogenic effects. Collectively, our findings elucidate the functional significance of SNHG15 driving metabolic reprogramming through the PGK1-PDK1-PDHE1α axis in HCC and identify this pathway as a potential therapeutic target for clinical intervention.