Deciphering Risperidone-Induced Lipogenesis by Network Pharmacology and Molecular Validation.

Area of Science:

• Pharmacology
• Molecular Biology
• Biochemistry

Background:

• Risperidone, an atypical antipsychotic, is known to cause significant weight gain.
• The precise molecular mechanisms and pharmacological targets underlying risperidone-induced lipogenesis (RIL) require further investigation.

Purpose of the Study:

• To elucidate the action mechanisms of risperidone-induced lipogenesis (RIL) using network pharmacology and experimental validation.
• To identify and validate potential signaling pathways involved in RIL.

Main Methods:

• Integrated network pharmacology, transcriptomics, molecular docking, and molecular experiments.
• Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for signaling pathway identification and validation.
• Experimental validation using Oil Red O staining and RT-PCR to assess adipocyte differentiation and lipid accumulation.

Main Results:

• Risperidone promotes adipocyte differentiation and lipid accumulation.
• Network pharmacology and GO analysis indicated risperidone influences cellular metabolism, specifically adipocyte metabolism and differentiation.
• Transcriptome analysis revealed risperidone impacts lipid accumulation-related functions. Pathway analysis identified targeting of MAPK14, MAPK8, and RXRA, leading to inhibition of long-chain fatty acid β-oxidation via decreased STAT3 expression and phosphorylation.

Conclusions:

• Risperidone increases adipocyte lipid accumulation.
• This effect is plausibly mediated by the inhibition of long-chain fatty acid β-oxidation.
• The mechanism involves targeting MAPK14 and MAPK8.