The Active Components of Traditional Chinese Medicines Regulate the Multi-Target Signaling Pathways of Metabolic Dysfunction-Associated Fatty Liver Disease

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD), which is characterized by hepatocyte lipid accumulation driven by systemic metabolic dysregulation, represents a critical therapeutic challenge in the context of the global metabolic syndrome epidemic. The clinically recommended drugs for MAFLD mainly include antioxidants, hepatoprotective anti-inflammatory drugs, and weight-loss drugs. However, the mechanisms underlying the progression of MAFLD is characterized by nonlinearity, highlighting the urgent need for safer multi-target alternative therapies. Although existing single-target pharmacological interventions often show limited efficacy and adverse effects, the multi-component and multi-target nature of the active ingredients in traditional Chinese medicine (TCM) formulations represent new opportunities for systemic metabolic regulation. In this study, by searching PubMed and Web of Science, we identified 108 experimental studies. By evaluating multiple mechanisms, such as improving lipid metabolism and insulin resistance, alleviating oxidative stress damage, inhibiting liver inflammation, suppressing liver fibrosis, reducing endoplasmic reticulum stress, regulating hepatocyte autophagy, inhibiting hepatocyte apoptosis, improving mitochondrial dysfunction, and regulating the intestinal flora, we constructed a cross-scale regulatory network for the treatment of MAFLD by the active components of TCM. Subsequently, the dynamic target groups were screened, and a new paradigm of "mechanism-oriented and spatiotemporal-optimized" design for TCM compound prescriptions was proposed, providing a theoretical framework for the development of precise therapies that can improve liver lipid metabolism, block inflammation and fibrosis, and restore intestinal homeostasis.

Keywords: action mechanism; active ingredient; lipid metabolism disorder; metabolic dysfunction-associated fatty liver disease; traditional Chinese medicine.

Figure 1

The progression of MAFLD and its non-linear characteristics.Upon activation, TGF-β collaborates with Wnt/β - catenin through Smad3 to promote fibrosis. The inactivation of the Hippo pathway leads to the nuclear translocation of YAP/TAZ, which then activates the PI3K/AKT/mTOR pathway, accelerating tumor progression. (a)TGF-β/Smad, Action stages: Hepatic Fibrosis (HF). (b) Wnt/β-catenin, Action stages: Non - alcoholic Steatohepatitis (NASH), Hepatocellular Carcinoma (HCC). (c) Hippo/YAP/TAZ, Action stages: HF, HCC. (d) PI3K/AKT/mTOR, Action stages: NASH, HCC. (e) Nrf2/ARE, Action stages: MAFLD, NASH.

Figure 2

Classification basis of MAFLD of active ingredients of traditional Chinese medicine *, To increase, promote, or increase;#, To reduce, inhibit, or reduce. (a) Improve lipid metabolism disorders and insulin resistance: AMPK, PPARα, SREBP-1c, PPAR-γ, FXR, SIRT1, PGC-1α, LXRα, PI3K, AKt. (b) Relieve oxidative stress: Nrf2/HO-1, GSH-Px. (c) Inhibit liver inflammation: NF-κB, TNF-α. (d) Inhibit liver fibrosis: Smad3, Smad4, HSC, COLIII. (e) Relieve endoplasmic reticulum stress: PERK, JNK, Endoplasmic reticulum stress signature protein. (f) Regulate autophagy of hepatocytes: mTOR, Autophagy associated proteins. (g) Inhibition of hepatocyte apoptosis: Bcl-2, Bax. (h) Improve mitochondrial dysfunction: Mitochondrial β oxidation, Mitochondrial respiratory chain. (i) Improve intestinal flora imbalance: Ruminococcaceae, Lachnospiraceae, Desulfovibrio, Dubosiella.

Figure 3

Mechanism of action of Chinese medicine active ingredients in treatment of MAFLD. Core early intervention targets: (a) SREBP-1c/ACC/FAS/SCD-1, reduce lipid accumulation at the source, and block the subsequent triggering of oxidative stress and fibrosis. (b) AMPK, activating AMPK can achieve dual regulation:1.Inhibit lipid synthesis (by phosphorylating ACC and SREBP-1c).2.Promote autophagy (the LC3 marker increases → clear lipids and damaged proteins). (c) LSECs-HSC, if the inactivation of liver sinusoidal endothelial cells (LSECs) is the initial trigger for the activation of hepatic stellate cells (HSCs), restoring the function of LSECs can fundamentally prevent the initiation of fibrosis. (d) IRE1α/PERK/Nrf2, alleviate the mitochondrial dysfunction and oxidative damage caused by lipid accumulation. Priority ranking: SREBP-1c/ACC/FAS>AMPK>LSECs-HSC>IRE1α/PERK/Nrf2>Bcl-2.