Modulatory Role of Traditional Chinese Medicine in Gut–Liver and Adipose–Liver Axis Dysfunction in MASLD

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease worldwide, affecting around 24% of the population, with regional prevalence ranging from 31.8% in the Middle East to 13.5% in Africa (WHO). MASLD encompasses a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Its complex pathogenesis involves insulin resistance, obesity, genetic factors, and chronic inflammation, leading to excessive lipid accumulation in hepatocytes. Current Western treatments primarily address symptoms but offer limited efficacy. Traditional Chinese Medicine (TCM) provides a holistic approach focused on restoring Yin-Yang balance and Qi flow, viewing liver dysfunction as related to dampness and Qi stagnation. Modern research supports TCM’s multi-target actions, showing herbal medicines improve gut microbiota, strengthen the intestinal barrier, reduce inflammation, and modulate adipokines and insulin sensitivity. These mechanisms support TCM’s potential systemic efficacy in managing MASLD, integrating traditional theory with modern pharmacology. A systematic literature search was conducted across major databases including PubMed, Scopus, and Web of Science to identify relevant preclinical and clinical studies published up to 2025. The search strategy employed combinations of keywords such as “Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD),” “Traditional Chinese Medicine (TCM),” “gut-liver axis,” “adipose-liver axis,” “herbal medicine,” “gut microbiota,” and “adipokines.” Studies were included if they investigated molecular mechanisms or therapeutic effects of Chinese herbal medicines in MASLD models, particularly focusing on modulation of the gut-liver and adipose tissue-liver axes. Both in vitro and in vivo experimental studies, as well as relevant clinical trials, were considered. Studies were excluded if they were non-English, case reports, reviews without original data, or lacked mechanistic or therapeutic relevance. This approach aimed to ensure a comprehensive and focused synthesis of high-quality evidence supporting the systemic effects of TCM in MASLD. Recent studies highlight the gut-liver and adipose-liver axes as key contributors to MASLD progression. Gut dysbiosis alters bile acids, tryptophan catabolites, and BCAAs, where Bacteroides species promote secondary bile acid accumulation, disrupting FXR signaling and causing lipid imbalance and inflammation. Tryptophan-derived indoles impair gut barrier integrity, worsening liver inflammation and fibrosis, while elevated BCAAs associate with insulin resistance and hepatocyte damage. Obesity-induced adipose dysfunction drives MASLD by releasing excess FFAs, activating NF-κB and PPAR-γ pathways, and secreting pro-inflammatory cytokines (TNF-α, IL-6), further impairing insulin sensitivity. Multiple Traditional Chinese Medicine (TCM) formulations show therapeutic potential in preclinical MASLD models by modulating these axes. Si Miao San increased Lactobacillus and Bifidobacterium while reducing Firmicutes and Proteobacteria , improving microbiota balance and reducing liver steatosis. TiaoGanXiaoZhi enhanced intestinal barrier integrity and reduced systemic inflammation. Jiangzhi Capsule inhibited hepatic lipid accumulation by downregulating SREBP pathways. These findings support TCM’s multi-target mechanisms in improving gut microbiota composition, enhancing barrier function, reducing inflammation, and regulating lipid metabolism in MASLD. This review demonstrates that TCM offers a multi-target approach to MASLD management by modulating critical metabolic and inflammatory pathways, particularly the gut-liver and adipose tissue-liver axes. These mechanisms align with modern pharmacological findings, providing a scientific basis for ancient medical practices. However, clinical evidence remains limited, and standardized, high-quality clinical trials are needed to validate the efficacy and safety of specific herbal interventions. Future research should focus on elucidating precise molecular targets and optimizing formulation strategies to enhance clinical translation of TCM-based treatments for MASLD. This graphical abstract illustrates the role of Traditional Chinese Medicine (TCM) formulations in modulating the gut–liver axis and regulating the adipose tissue–liver axis to prevent the progression Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) . On the left, a healthy liver is shown, whereas on the right, the pathological transition to MASLD is depicted. In the gut–liver axis, microbial imbalance, increased intestinal permeability, and endotoxin leakage activate inflammatory pathways, such as the TLR4/NF-κB and NLRP3 inflammasome, contributing to liver injury. Disruption of bile acid metabolism and signaling via receptors like FXR, FGF19, and TGR5 further promote steatosis and inflammation. Several TCM formulations including Da-Chai-Hu Decoction (DCHD), Qingre Huazhuo Jiangzhi Formula (QHF), Lingguizhugan Decoction (LGZG), Shenling Baizhu San (SLBZS), and Qushi Huayu Decoction (QHD) are highlighted for their capacity to restore gut microbiota balance, reduce endotoxemia, and regulate bile acid pathways. In the adipose tissue–liver axis, excessive fat accumulation and dysregulated adipokine secretion lead to insulin resistance and chronic inflammation. Key pathways involved include the adiponectin–AMPK pathway, leptin–JAK/STAT pathway, IRS/PI3K/AKT signaling, PPAR-α/β regulation, and TNF-α/JNK activation, all of which contribute to hepatic fat deposition and inflammation. TCM formulations such as Danshen–Gegen Decoction (DGD), Jiangzhi Granule (JZG), Shengqi Jiangtang Decoction (SQJTD), Xuefu Zhuyu Decoction (XFZYD), and Erchen Decoction (ECD) are shown to improve insulin sensitivity, reduce lipid accumulation, and suppress inflammatory responses. Overall, the figure emphasizes that targeting these two interlinked axes with TCM can provide a holistic therapeutic approach to mitigate MASLD progression , by balancing metabolism, restoring gut–liver homeostasis, and regulating adipose–liver signaling.