In the EU, 15 million people annually take systemic glucocorticoids. Glucocorticoids, which bind to the glucocorticoid receptor (GR), are effective but may cause serious side effects, including insulin resistance and dyslipidemia, underscoring the need for alternative therapeutic strategies. Interestingly, peroxisome-proliferator activated nuclear receptor α (PPARα) agonism counteracts symptoms similar to glucocorticoid side effects. Therefore, our aim is to explore the potential of inducing nuclear receptor crosstalk between GR and PPARα to suppress inflammation while inducing fewer metabolic (side) effects. We previously found that when combined, GR and PPARα agonists have additive to synergistic anti-inflammatory activities in cellular and murine models, but lack the adverse effects on glucose and lipid metabolism. In future studies, we will further investigate the benefit of inducing GR-PPARα crosstalk in male and female mice in a rheumatoid arthritis model, monitoring immunomodulatory and metabolic (side) effects. We will additionally measure the degree of induced heterodimer formation by developing more sensitive molecular tools based on NanoBit technology. Finally, we will explore novel pharmacological tools to induce GR-PPARα crosstalk and characterize the anti-inflammatory and metabolic profile hereof. In conclusion, inducing crosstalk between GR and PPARα may be an interesting therapeutic strategy to suppress inflammation while inducing fewer metabolic side effects, which will be the subject of research for future studies.