Coordinated epigenetic dysregulation of CNR1 and FAAH genes drives endocannabinoid system dysfunction in anorexia nervosa

Sep 29, 2026

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Anorexia nervosa (AN) remains a severe psychiatric disorder with limited biomarkers for diagnosis and treatment monitoring. Integrated epigenetic and genetic analysis in saliva investigated endocannabinoid system (ECS) dysregulation by assessing DNA methylation of CNR1 and FAAH, genetic polymorphisms, and exosomal microRNAs targeting these genes in AN patients versus controls. Results reveal coordinated promoter hypermethylation/hypomethylation that impairs endocannabinoid signaling, supported by compensatory miRNA responses and superior combined biomarker diagnostic precision.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Plain English summary

Keywords

Background (disease context)

Diagnosis challenges

Proposed biomarkers

Gilardini et al. Journal of Eating Disorders (2026) 14:5 [https://doi.org/10.1186/s40337-025-01472-y](https://doi.org/10.1186/s40337-025-01472-y) Journal of Eating Disorders RESEARCH Open Access Coordinated epigenetic dysregulation of CNR1 and FAAH genes drives endocannabinoid system dysfunction in anorexia nervosa Federica Gilardini 1,2, Francesca Mercante 1, Annalaura Sabatucci 1, Mariangela Pucci 1, Carlo Cifani3, Cristina Segura-Garcia4,5, Marianna Rania5* and Claudio D’Addario 1,6* Abstract Background Anorexia nervosa (AN) is a severe psychiatric disorder with limited biomarkers for diagnosis and treatment monitoring. We investigated endocannabinoid system (ECS) dysregulation in AN through integrated epigenetic and genetic analysis of saliva. Methods We analyzed DNA methylation patterns of cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes, characterized genetic polymorphisms, and quantified expression of exosomal microRNAs targeting these genes in AN patients versus healthy controls. Results We discovered a novel bidirectional epigenetic dysregulation of the ECS: CNR1 promoter hypermethylation coupled with FAAH promoter hypomethylation. This dual-target mechanism systematically impairs endocannabinoid signaling by simultaneously reducing receptor availability while increasing endocannabinoid degradation. Compensatory miRNA responses (upregulated miR-342-3p, miR-23b-3p targeting CNR1; upregulated miR-4505, miR- 1275 targeting FAAH) revealed dynamic regulatory attempts to counterbalance these primary epigenetic changes. This convergent pathway dysfunction demonstrates how multiple molecular mechanisms work in concert todysregulate appetite regulation in AN. Combined biomarker panels showed superior diagnostic precision compared to individual markers. Conclusions Our findings establish this bidirectional epigenetic dysregulation as a central mechanism underlying ECS dysfunction in AN, providing mechanistic insights that identify novel therapeutic targets and advance precision medicine approaches for this challenging disorder. Plain English summary This study identifies biological markers in saliva that may help detect anorexia nervosa more accurately. We analyzed specific genes involved in the endocannabinoid system—a network in the body that helps regulate appetite, mood, and reward—suggesting patterns that could improve diagnosis and reveal new treatment targets. By identifying these gene patterns in saliva, we offer a non-invasive way to better understand how anorexia *Correspondence: Marianna Rania [marianna.rania@aourenatodulbecco.it](marianna.rania@aourenatodulbecco.it)[ ](marianna.rania@aourenatodulbecco.it)Claudio D’Addario cdaddario@unite.it Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Gilardini et al. Journal of Eating Disorders (2026) 14:5 Page 2 of 14 develops and pr

FAQs

What was the study investigating in anorexia nervosa?

The study investigated endocannabinoid system (ECS) dysregulation in anorexia nervosa using integrated epigenetic and genetic analysis of saliva.

Which genes and molecular layers were analyzed?

DNA methylation patterns of the CNR1 and FAAH genes were examined, genetic polymorphisms were characterized, and exosomal microRNAs targeting these genes were quantified.

What key epigenetic mechanism did the researchers find?

A bidirectional epigenetic dysregulation was found: CNR1 promoter hypermethylation coupled with FAAH promoter hypomethylation, impairing endocannabinoid signaling by reducing receptor availability while increasing endocannabinoid degradation.

Sep 29, 2026

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