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Adipose Tissue_Appetite_and Obesity

SUN-711 - Non-Psychedelic Psilocin Derivative Induces Beneficial Hepatic Lipidome Remodeling and Metabolic Improvement in Diet-Induced MASLD

Sunday, June 14, 2026
9:00 AM - 4:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Lucia Centofanti, MSc: No financial relationships to disclose
Franco Folli, MD, PhD: No relevant disclosure to display

Background In a diet-induced model of MASLD, chronic low dose psilocybin (a serotonin analogue that binds 5-HT receptors) reduced liver steatosis, limited body weight (BW) gain, and improved glucose and lipid homeostasis. Chemical modification strategies aimed at limiting central nervous system exposure, such as PEGylation, may further enhance the therapeutic potential of serotonergic compounds by preserving peripheral activity while minimizing psychoactive effects.

Methods The effect of psilocin conjugates with polyethylene-glycols (PEG-8-psilocin) was tested in male C57BL/6 mice fed a high-fat (60% kcal from fat), high-fructose (30% in drinking water) diet (HFHFD) for 17 weeks. The treatment group (n = 8) received 0.05 mg/kg*bw of PEG-8-psilocin orally daily, while the control groups received a vehicle (n = 8) or equiv. dose of psilocybin (n = 8). Mice fed a standard diet (n = 8) were used as healthy controls. Hepatic lipid composition was characterized by untargeted LC-MS/MS analysis. Pancreatic ultrastructure was examined by transmission electron microscopy (TEM).

Results PEG-8-psilocin maintained psilocybin-like activity at 5-HT receptors and was well-tolerated in rats. Chronic treatment with PEG-8-psilocin, similarly to psilocybin, resulted in marked reduction of liver steatosis and significantly reduced BW gain vs healthy mice (p < 0.01 for PEG-8-psilocin). At lipidomic analysis, PEG-8-psilocin restored hepatic diglycerides and triglycerides (both normal and oxidized forms) back to healthy control levels. PEG-8-psilocin restored normal levels of ceramides and dihydroceramides. Ultrastructural analysis of HFHFD mice, compared to those of control mice, showed β cells secretory granules with a reduced dense content, enlarged reticulum and Golgi apparatus cysternae and swollen mitochondria with irregular christae. In mice treated with PEG-8-psilocin, β cells showed restoration of insulin secretion cells number to normal levels. In these cells, moreover, mitochondria were big, with regular christae, and Golgi apparatus cysternae were well developed.

Conclusions PEG-8-psilocin induced a beneficial remodeling of the hepatic lipidome in MASLD, reducing lipotoxic lipid species and improving insulin sensitivity, glucose tolerance, and reducing body weight, and improved β-cell ultrastructure without central nervous system effects. These results support peripheral serotonergic modulation as a novel therapeutic approach for metabolic liver disease.