2. Academic Validation
  3. Dual pharmacological targeting of coactivator-associated arginine methyltransferase 1 (CARM1) and salt inducible kinase (SIK) drives ketogenesis in both hepatocytes and mice

Dual pharmacological targeting of coactivator-associated arginine methyltransferase 1 (CARM1) and salt inducible kinase (SIK) drives ketogenesis in both hepatocytes and mice

  • Br J Pharmacol. 2026 Aug;183(15):4399-4415. doi: 10.1111/bph.70447.
Tábata Bergonci 1,  Troels Kjær Rosenbæk 1,  Samuel J Windross 1,  Ulrik B Keiding 1 2,  Estéfano Pinilla 3,  Katrine P Stuckert 1,  Jakob Hansen 1,  Camilla B Nielsen 1,  Jemila Peter Gomes 1 4,  Lucy R Davies 5,  Johan Palmfeldt 4,  Volker Loeschcke 5,  Charlotte U Andersen 1 3 6,  Ulf Simonsen 3,  Thomas B Poulsen 2,  Mogens Johannsen 1
Affiliations

Affiliations

  • 1 Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.
  • 2 Department of Chemistry, Aarhus University, Aarhus, Denmark.
  • 3 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 4 Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • 5 Department of Biology, Aarhus University, Aarhus, Denmark.
  • 6 Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.
PMID: 42055601 DOI: 10.1111/bph.70447
Abstract

Background and purpose: Ketone bodies are liver-derived circulating energy metabolites that positively impact most hallmarks of ageing. Ketone bodies increase during calorie restriction and fasting, two of the more widely perceived methods to increase health span. Adhering to a strict diet to increase ketogenesis is demanding, which leaves a significant unmet need for a pharmacological alternative. The present study hypothesised that chemical genetic screening can reveal novel proteins that will regulate ketogenesis.

Experimental approach: We developed phenotypic screening assays to determine ketone bodies in hepatocytes. We applied two libraries of annotated small molecule compounds to determine proteins regulating ketogenesis. Adenosine 3',5' cyclic monophosphate (cAMP) measurements, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blotting and small interfering RNA (siRNA) silencing were performed to validate targets in hepatocytes. RT-qPCR and proteomics were performed to validate targets in liver tissues. Drosophila melanogaster was used in a longevity assay. Mice were used to demonstrate regulation of ketogenesis in vivo.

Key results: Ketogenesis links pathways involved in metabolic health and longevity, identifying coactivator-associated arginine methyltransferase 1 (CARM1) as a novel regulator. Joint pharmacological targeting of CARM1 and salt inducible kinases (SIK) synergise, resulting in high ketogenic induction in hepatocytes. Finally, we demonstrate the dual activation of ketogenesis with homeostatic blood-glucose in non-fasting mice.

Conclusion and implications: Ketogenesis represents a promising biomarker and therapeutic target for metabolic interventions targeting age-related diseases. Our data suggest that CARM1 and SIKs warrant further investigation for pharmacological induction of ketogenesis, with potential clinical applications in ageing-associated metabolic dysfunction.

Keywords

ReactELISA; cAMP signalling; chemical genetics; drug screening; hepatocytes; ketogenesis.

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