Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm

Xiao-Jie Li; Le Chang; Yang Mi; Ge Zhang; Shan-Shan Zhu; Yue-Xiao Zhang; Hao-Yu Wang; Yi-Shuang Lu; Ye-Xuan Ping; Peng-Yuan Zheng; Xia Xue

doi:10.1016/j.joim.2025.06.003

Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm

J Integr Med. 2025 Jun 14:S2095-4964(25)00083-4. doi: 10.1016/j.joim.2025.06.003. Online ahead of print.

Authors

Xiao-Jie Li¹, Le Chang¹, Yang Mi¹, Ge Zhang², Shan-Shan Zhu³, Yue-Xiao Zhang¹, Hao-Yu Wang¹, Yi-Shuang Lu¹, Ye-Xuan Ping¹, Peng-Yuan Zheng⁴, Xia Xue⁵

Affiliations

¹ Henan Key Laboratory for Helicobacter pylori and Digestive Tract Microecology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China; Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science, Zhengzhou 450000, Henan Province, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, Henan Province, China.
² Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China; Henan Key Laboratory of Chronic Disease Prevention and Therapy & Intelligent Health Management, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China.
³ Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China.
⁴ Henan Key Laboratory for Helicobacter pylori and Digestive Tract Microecology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China; Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science, Zhengzhou 450000, Henan Province, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, Henan Province, China. Electronic address: pyzheng@zzu.edu.cn.
⁵ Henan Key Laboratory for Helicobacter pylori and Digestive Tract Microecology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China; Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science, Zhengzhou 450000, Henan Province, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, Henan Province, China. Electronic address: xue-xiasophia@hotmail.com.

PMID: 40581550
DOI: 10.1016/j.joim.2025.06.003

Abstract

Objective: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity.

Methods: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes.

Results: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1.

Conclusion: We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; Epub ahead of print.

Keywords: Circadian rhythm disruption; Hepatocellular carcinoma subtypes; Omics; Personalized treatment; Precise medicine.