Abstract Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease marked by lipid accumulation, inflammation, and fibrosis that can advance to hepatocellular carcinoma. While both de novo lipogenesis (DNL) and innate immune activation drive disease progression, their mechanistic connection remains unclear. Here, we identified DYRK1A as a novel kinase that activates STING-dependent inflammatory signaling and links metabolic and immune dysregulation in MASH. Methods: MASH and fibrosis models were established in both cellular and animal systems. DYRK1A expression was modulated through knockdown, overexpression, and pharmacological inhibition. Lipogenesis, STING activation, lipotoxicity, and fibrosis were assessed using molecular assays, histopathology, and serum injury markers. Results: DYRK1A expression was elevated by approximately 40% in cellular models of MASH compared with controls. Further, we confirmed DYRK1A overexpression reduced phosphorylation of AMPK and ACC, enhancing lipogenic flux and elevating lipid accumulation, supporting its potential involvement in metabolic regulation. Conversely, DYRK1A silencing or inhibitor treatment suppressed DNL, destabilized STING, and mitigated lipotoxicity by reducing the phosphorylation of STING, TBK1 and IRF3, as confirmed by Oil Red O staining and immunoblotting. In vivo, DYRK1A was markedly elevated in MASH-associated fibrosis, whereas its inhibition reduced hepatic triglyceride deposition (∼30%), collagen remodeling (∼30%), and serum AST/ALT levels (∼40%), indicating improved liver function. Consistent with in vitro results, inhibitor-treated livers exhibited diminished DNL- and STING-related proteins expression, underscoring DYRK1A as a newly identified key driver of metabolic inflammation and fibrosis. Conclusions: This study defines a novel DYRK1A-mediated lipogenic-inflammatory cascade linking metabolic stress to innate immune activation and fibrosis in MASH. Targeting DYRK1A may provide a therapeutic strategy to disrupt the lipogenesis-STING axis, alleviate chronic metabolic liver injury, and potentially prevent progression to hepatocellular carcinoma. Citation Format: Wen Yan Huang, Kyunghee Noh, . Targeting a DYRK1A-regulated lipogenesis-STING axis alleviates hepatic metabolic dysfunction and lipotoxicity in metabolic steatohepatitis 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 7332.
Huang et al. (Fri,) studied this question.