Letter to the Editor: Hepatic transcriptome and metabolome analysis of Jiangtang Tiaozhi formula

Abstract

Jiangtang Tiaozhi formula (JTTZF) has been widely used in the management of glycolipid metabolic disorders, yet its underlying molecular mechanisms remain incompletely understood. Tian et al recently published a study in the World Journal of Diabetes, which reported a comprehensive hepatic transcriptomic and metabolomic analysis that provides important insights into the regulatory effects of JTTZF on glucose and lipid homeostasis. This multi-omics strategy offers a valuable systems-level perspective on the pharmacological actions of this traditional Chinese medicine formulation. In this commentary, we highlight the strengths of the study and discuss several aspects that warrant further investigation to enhance mechanistic depth and translational relevance. These include dose-response relationships, cellular heterogeneity, causal validation of key pathways, identification of active constituents, and long-term safety evaluation. We also emphasize the potential role of host-related factors, such as immune regulation and gut microbiota-associated metabolic interactions, in influencing therapeutic responsiveness.

Key Words: Glycolipid metabolic disorder; Jiangtang Tiaozhi formula; Hepatic transcriptome; Hepatic metabolome; Multi-omics analysis; Insulin resistance; Lipid metabolism; Glucose metabolism

Core Tip: This commentary discusses a recent hepatic transcriptomic and metabolomic study that elucidates the regulatory effects of Jiangtang Tiaozhi formula on glycolipid metabolism. We emphasize key strengths of the multi-omics strategy and highlight critical issues that warrant further investigation, including dose-response relationships, cellular resolution, mechanistic causality, active constituent identification, and long-term safety evaluation. By integrating systems biology and translational perspectives, this work underscores the potential of traditional Chinese medicine-based therapies to advance precision medicine approaches for metabolic disorders.

TO THE EDITOR

We read with great interest the article published in the World Journal of Diabetes by Tian et al[1] entitled “Integrated hepatic transcriptome and metabolome reveal the mechanisms of Jiangtang Tiaozhi formula on improving glycolipid metabolic disorder”. This study provides a comprehensive and well-executed multi-omics investigation into the hepatoprotective and metabolic regulatory effects of Jiangtang Tiaozhi formula (JTTZF) in a high-fat diet-induced mouse model. By integrating hepatic transcriptomic and metabolomic analyses, the authors systematically delineate key pathways involved in lipid oxidation, glucose metabolism, inflammatory regulation, and energy homeostasis, thereby offering valuable mechanistic insights into the therapeutic basis of this traditional Chinese medicine formulation.

The strength of this work lies in its robust experimental design and its integrative analytical framework. The combined use of RNA sequencing and untargeted metabolomics enables the identification of coordinated changes in metabolic pathways, moving beyond single-gene or single-metabolite observations. Importantly, the authors validate representative transcriptomic findings by quantitative PCR, which further reinforces the reliability of their omics-based conclusions. Collectively, this study represents a meaningful step toward the modernization and mechanistic clarification of traditional Chinese medicine in the context of metabolic disorders.

Nevertheless, several aspects warrant further discussion to enhance the translational relevance and mechanistic depth of the findings.

First, the current study employs a single-dose regimen of JTTZF based on human-to-mouse dose conversion[2]. While this approach is reasonable for an initial mechanistic investigation, the absence of a dose-response evaluation limits interpretation of therapeutic potency, safety margins, and optimal exposure. Dose-dependent effects are particularly important for multi-component herbal formulas, in which distinct constituents may exert differential or even opposing biological activities at varying concentrations. Incorporating multiple dosage levels in future studies would help clarify whether the observed transcriptomic and metabolomic changes scale proportionally with treatment intensity.

Second, although the liver is a central metabolic organ and an appropriate focus for this investigation, hepatic tissue is composed of diverse cell populations, including hepatocytes, Kupffer cells, hepatic stellate cells, and endothelial cells. Bulk transcriptomic analyses cannot resolve whether the observed gene expression changes originate predominantly from parenchymal cells or from non-parenchymal immune and stromal compartments. Single-cell RNA sequencing or spatial transcriptomics could substantially refine these findings by identifying the specific target cell populations responsive to JTTZF, thereby improving mechanistic precision and guiding future therapeutic targeting strategies[3].

Third, the integrative transcriptome-metabolome associations presented in this study are inherently correlative. While the coordinated regulation of genes and metabolites strongly suggests functional linkage, direct causal relationships remain to be established. For example, whether specific transcriptomic changes drive downstream metabolic remodeling, or whether altered metabolite levels secondarily influence gene expression, cannot be conclusively determined from the current design. Targeted perturbation experiments, such as genetic manipulation of key regulatory genes or pharmacological modulation of candidate metabolites, would be valuable to validate causality within the proposed regulatory networks.

Fourth, JTTZF is a complex formulation composed of multiple herbal constituents, each potentially containing numerous bioactive compounds. The present study convincingly demonstrates system-level metabolic effects but does not address which specific components or compound classes are primarily responsible for the observed molecular changes. Future studies integrating network pharmacology, compound-target prediction, or targeted metabolite-protein interaction analyses could help identify the principal active ingredients and their direct molecular targets, thereby facilitating quality control, standardization, and regulatory evaluation[4].

Fifth, the findings are derived from a single metabolic disease model based on high-fat diet-induced glycolipid metabolic disorder. Although this model captures key features of insulin resistance and dyslipidemia, metabolic diseases in humans are highly heterogeneous. Validation across additional models, such as genetic obesity models or models incorporating inflammatory or aging-related components, would help determine the generalizability of JTTZF’s metabolic effects.

Finally, while JTTZF has a history of clinical use, systematic evaluation of potential biological toxicity and off-target effects at the molecular level is essential for translational advancement. Long-term administration studies, coupled with comprehensive organ-specific transcriptomic or metabolomic safety profiling, would further strengthen confidence in its clinical applicability.

In addition, emerging evidence highlights the gut microbiota as a critical regulator of host metabolism, systemic inflammation, and immune homeostasis in type 2 diabetes. Microbiota-immune-metabolic interactions have been increasingly recognized as important contributors to therapeutic responsiveness and disease heterogeneity, thereby adding another layer of host-related complexity that may influence the translational performance of traditional Chinese medicine-based interventions[5].

In summary, Tian et al[1] present a rigorous and informative multi-omics study that substantially advances our understanding of how JTTZF ameliorates glycolipid metabolic disorder through coordinated regulation of hepatic gene expression and metabolic pathways. Addressing the points discussed above—particularly dose-response relationships, cellular resolution, mechanistic causality, and active constituent identification—will further enhance the mechanistic clarity and translational impact of this important work. We commend the authors for their contribution and believe that their study provides a solid foundation for future precision medicine-oriented investigations of traditional Chinese medicine-based metabolic therapies.