Apremilast attenuates hepatic steatosis and metabolic dysfunction in a murine model of MASLD: Implications for patients with Psoriatic disease.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of morbidity, linked to obesity, type 2 diabetes, and cardiovascular disease. Psoriatic disease (PsD), a chronic inflammatory condition, often coexists with MASLD, exacerbating systemic inflammation and cardiometabolic risk. Apremilast, a selective PDE4 inhibitor approved for PsD, may provide additional metabolic benefits by improving weight, lipid metabolism, and insulin sensitivity.

OBJECTIVE

To evaluate the effects of apremilast on metabolic dysfunction, hepatic steatosis, and systemic inflammation in PsD patients with metabolic comorbidities, and to investigate mechanistic impact in a murine model of diet-induced MASLD.

METHODS

Twenty PsD patients treated with apremilast were stratified by metabolic comorbidities. Glucose metabolism and liver function were monitored for 6 months. In parallel, C57BL/6 J mice were fed chow or GAN diet. After 14 weeks, apremilast (10 mg/kg/day) was administered for two weeks. Body weight, adiposity, liver biomarkers, insulin resistance, histology, and proteomics were evaluated.

RESULTS

In PsD patients with comorbidities, apremilast reduced fasting insulin, HOMA-IR, transaminases, and the hepatic steatosis index. GAN-fed mice developed steatosis, increased fat mass, and elevated alanine aminotransferase (ALT) and HOMA-IR levels. Apremilast reduced body weight, ALT, insulin resistance, and hepatic fat. Histology confirmed a decrease in fibrosis. Proteomic profiling showed modulation of inflammatory, fibrotic, and lipid metabolic pathways, partially reversing GAN-induced proinflammatory signatures in liver, adipose tissue, and muscle.

CONCLUSIONS

Apremilast ameliorates hepatic dysfunction, improves insulin sensitivity, and reduces systemic metabolic dysfunction in a murine MASLD model. These findings support its therapeutic potential in PsD patients with metabolic disease, offering both anti-inflammatory and metabolic benefits.