Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains a leading cause of cancer-related mortality worldwide owing to its aggressive growth, high metastatic potential, and frequent recurrence. Increasing evidence indicates that metabolic reprogramming, particularly dysregulated lipid metabolism, plays a central role in HCC progression by supporting tumor proliferation, invasion, and survival. However, the molecular mechanisms linking aberrant lipid metabolism to HCC development remain incompletely understood, limiting the identification of effective therapeutic targets.

In a recent study in Genes & Diseases, researchers from Chongqing Medical University, Binzhou Central Hospital, Xi'an No. 1 Hospital, Hangzhou Medical College, and Changdu People's Hospital of Xizang investigated the role of adenosine deaminase acting on RNA 1 (ADAR1) in regulating lipid metabolic pathways in HCC and evaluated the therapeutic potential of the adenosine analogue 8-chloroadenosine (8-Cl-Ado) in suppressing tumor progression.

The authors employed an integrated multi-omics strategy combining publicly available single-cell RNA sequencing datasets, transcriptomic analyses, clinical HCC specimens, and in vitro cellular models. Bioinformatic analyses revealed that ADAR1 was markedly overexpressed in proliferating tumor cell populations and in HCC tissues compared with normal liver tissue. Functional studies demonstrated that elevated ADAR1 expression promoted HCC cell proliferation, migration, and invasion, suggesting that ADAR1 functions as a driver of malignant progression. Conversely, treatment with 8-Cl-Ado reduced ADAR1 expression in a dose- and time-dependent manner, indicating that this small-molecule compound may therapeutically target the ADAR1 signaling axis.

To elucidate the underlying molecular mechanisms, the authors performed transcriptomic profiling following 8-Cl-Ado treatment. Differential gene expression analyses revealed significant suppression of genes involved in cholesterol biosynthesis, fatty acid synthesis, and lipid metabolic pathways. Further mechanistic investigations demonstrated that ADAR1 directly binds to PPARγ mRNA, thereby activating PPAR signaling and promoting lipid metabolic reprogramming. PPARγ silencing markedly reduced malignant cellular behaviors, establishing its role in ADAR1-mediated tumor progression. Furthermore, rescue experiments showed that overexpression of the ADAR1 p150 isoform largely reversed the inhibitory effects of 8-Cl-Ado on tumor cell proliferation and invasion, providing strong evidence that the antitumor activity of 8-Cl-Ado is mediated through suppression of the ADAR1/PPARγ signaling axis.

The study further demonstrated that inhibition of ADAR1 signaling reduced intracellular lipid accumulation and downregulated multiple enzymes involved in fatty acid uptake, synthesis, esterification, and cholesterol production. These findings establish a direct mechanistic connection between ADAR1 activity and lipid metabolic remodeling in HCC, highlighting how disrupting this pathway can impair the metabolic adaptations required for tumor growth and dissemination. By integrating transcriptomic, molecular, and functional analyses, the researchers identify ADAR1 as a previously unrecognized regulator of PPARγ-dependent lipid metabolism in hepatocellular carcinoma.

In conclusion, this research provides the first evidence that 8-Cl-Ado suppresses HCC tumorigenesis and progression by inhibiting the ADAR1-PPARγ axis, thereby regulating lipid metabolic homeostasis. These findings identify a novel metabolic-epigenetic regulatory network, offering potential intervention strategies and therapeutic targets for the management of HCC.

Reference
Title of the original paper: 8-Chloroadenosine suppresses hepatocellular carcinoma progression via ADAR1/PPARγ axis-mediated lipid metabolism
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101874

Funding Information:
General Program of the Chongqing Natural Science Foundation (China) (No. CSTB2022NSCQ-MSX0909, CSTC2021JCYJ-MSXMX0158, CSTB2024NSCQ-MSX0179)
Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (China) (No. 2021240308)x
Group Medical Aid Project for the Tibet Autonomous Region, supported by the Natural Science Foundation of the Tibet Autonomous Region of China (No. XZ2023ZR-ZY75(Z))

# # # # # #

Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
Scopus CiteScore: 10.4 | Impact Factor: 14.6

# # # # # #

More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Diseases may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.cn
X (formerly twitter): @GenesNDiseases (https://x.com/GenesNDiseases)

# # # # # #