Mechanistic study of the cytotoxicity of cannabidiol and its metabolites in HepG2 cells.

Si Chen, Yuxi Li, Montserrat Puig, Frederic Moulin, Supratim Choudhuri, Jeremy Gingrich, Lei Guo

Abstract read

In one paragraph

Article in Archives of toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it

0cells of the map it votes in

0citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors.

Si ChenDivision of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR, 72079, USA. si.chen@fda.hhs.gov.ORCID 0000-0002-8872-311X

Yuxi LiDivision of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR, 72079, USA.

Montserrat PuigDivision of Pharmaceutical Quality and Research IV, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. FDA, Silver Spring, MD, 20993, USA.

Frederic MoulinDivision of Hepatology and Nutrition, Office of New Drugs, Center for Drug Evaluation and Research, U.S. FDA, Silver Spring, MD, 20993, USA.

Supratim ChoudhuriDivision of Food Ingredients, Office of Premarket Additive Safety, Office of Food Chemical Safety, Dietary Supplements, and Innovation, Human Foods Program, U.S. FDA, College Park, MD, 20740, USA.

Jeremy GingrichDivision of Food Ingredients, Office of Premarket Additive Safety, Office of Food Chemical Safety, Dietary Supplements, and Innovation, Human Foods Program, U.S. FDA, College Park, MD, 20740, USA.

Lei GuoDivision of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR, 72079, USA.

Funding

Intramural FDA HHS FD999999

6 · The paper itself

Abstract

The cannabidiol (CBD)-based drug, Epidiolex, received approval from the U.S. Food and Drug Administration (FDA) for treating seizures in certain childhood-onset epileptic disorders. CBD-associated liver toxicity is a serious side effect listed on the drug label. Our previous studies demonstrated cytotoxicity in primary human hepatocytes and HepG2 cells induced by CBD, 7-hydroxy-CBD, and 7-carboxy-CBD, with cell cycle disturbances, endoplasmic reticulum (ER) stress, and apoptosis identified as the underlying mechanisms. In this study, using a transcriptomic approach with mRNA-sequencing analysis, we found that downregulation of genes associated with oxidative phosphorylation and upregulation of genes associated with mitochondrial dysfunction, autophagy, and ER stress were among the top 10 canonical pathways consistently affected across different CBD concentrations. Direct measurement of the activity of the mitochondrial respiratory complexes that compose the oxidative phosphorylation process, demonstrated that CBD strongly inhibited Complexes IV and V and moderately inhibited Complexes II and III. CBD-induced mitochondrial dysfunction was indicated by a classic glucose-galactose assay, and the loss of mitochondrial membrane potential was confirmed by a JC-1 assay. Additionally, CBD induced autophagy, as evidenced by autophagosome formation and enhanced autophagic flux. Similar to CBD, 7-hydroxy-CBD induced a strong inhibition of Complexes IV and V, mitochondrial dysfunction, and autophagy, while 7-carboxy-CBD induced autophagy, with marginal inhibition on the respiratory complexes and no identified mitochondrial dysfunction. In summary, autophagy emerges as the common mechanism underlying CBD-, 7-hydroxy-CBD-, and 7-carboxy-CBD-induced cytotoxicity. Inhibition of mitochondrial respiratory complexes and mitochondrial dysfunction were observed with CBD and 7-hydroxy-CBD, but not with 7-carboxy-CBD.

Indexed as

CannabidiolMitochondria, LiverAutophagyElectron TransportHep G2 CellsHumansSequence Analysis, RNATranscriptomeCannabidiol7-Carboxy-CBD7-Hydroxy-CBDAutophagyCannabidiolCBDER stressLiver toxicityMitochondrial dysfunctionMitochondria respiratory complexesRNA-sequencing

Identifiers

PMID41272177

DOI10.1007/s00204-025-04236-4

PMCPMC12746337

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.