Therapeutic efficacy and multitarget mechanisms of traditional Chinese medicine in hereditary liver diseases: Insights into bioactive components

Abstract

Hereditary liver diseases (HLIDs) are a group of genetically driven disorders characterized by progressive hepatic dysfunction, multiorgan involvement, and limited therapeutic options. Traditional Chinese medicine (TCM) has a 2000-year legacy in liver disease management, with modern research highlighting its multitarget, multi-pathway pharmacological profile as a unique strength. This review synthesizes evidence on the potential therapeutic potential of TCM in HLIDs, focusing on: (1) The chemical diversity of hepatoprotective TCM components (alkaloids, flavonoids, terpenoids, etc.); (2) Their proposed mechanisms - from regulating metal ion homeostasis and oxidative stress to inhibiting nonapoptotic cell death (ferroptosis/pyroptosis) and remodeling the gut-liver axis; and (3) The translational value of compound TCM formulas (e.g., Gandouling Decoction) guided by the Jun-Chen-Zuo-Shi (sovereign-minister-assistant-messenger) principle. We also address current challenges (e.g., low bioavailability and quality control) and future directions (multiomics, nanotechnology, and rigorous randomized controlled trials). Our analysis underscores the potential of TCM to complement western medicine in HLID management by targeting root pathogenic links - a paradigm shift from symptom control to holistic, mechanism-based therapy.

Key Words: Hereditary liver diseases; Traditional Chinese medicine; Bioactive components; Multitarget mechanisms; Translational medicine

Core Tip: This review highlights the therapeutic potential of traditional Chinese medicine in hereditary liver diseases, emphasizing its proposed multitarget mechanisms, regulating ion homeostasis, oxidative stress, cell death, and gut-liver axis. It explores bioactive components (alkaloids and flavonoids) and compound formulas (e.g., Gandouling Decoction) guided by Jun-Chen-Zuo-Shi principles, addressing challenges (bioavailability and quality control) and future directions (multiomics and nanotechnology) to complement western medicine via holistic, mechanism-based therapy.

INTRODUCTION

Hereditary liver diseases (HLIDs) arise from germline mutations, leading to disrupted hepatic metabolism, toxic substance accumulation, and multiorgan damage. Key examples include Wilson’s disease (WD, copper overload), a1 antitrypsin deficiency (AATD, protein misfolding), hereditary hemochromatosis (HH, iron overload), and glycogen storage disease (GSD, metabolic dysregulation)[1-3]. While monogenic, HLIDs manifest as complex, systemic disorders: WD causes liver cirrhosis and neurodegeneration; AATD links liver fibrosis to emphysema; and HH drives iron-induced oxidative stress and hepatocellular carcinoma[4-6].

Current therapies are palliative, not curative: Chelators (e.g., D-penicillamine) for WD or phlebotomy for HH require lifelong use, with poor compliance and off-target effects (e.g., D-penicillamine exacerbates neurological symptoms)[7,8]. For AATD and GSD, no disease-modifying drugs exist - end-stage disease relies on liver transplantation, which is limited by donor shortages and cost[9,10]. A critical unmet need is targeted therapy addressing root genetic/pathogenic mechanisms.

With a 2000-year history in liver disease management (e.g., Huangdi Neijing describing jaundice and hypochondriac pain), the strength of traditional Chinese medicine (TCM) lies in holistic, multicomponent regulation[11,12]. Modern research translates this empiricism into science: High-resolution mass spectrometry identifies TCM components, network pharmacology maps their targets, and multiomics (transcriptomics and metabolomics) validates their mechanisms[13-15]. For HLIDs, TCM components act on multiple nodes of pathogenic cascades; for example, berberine chelates copper and activates nuclear factor erythroid 2-related factor 2 (Nrf2) to reduce oxidative stress; and salvianolic acid B (SalB) modulates iron metabolism and inhibits the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome[16,17].

This review distinguishes itself by integrating cutting-edge concepts [ferroptosis, gut-liver axis, and epithelial-mesenchymal transition (EMT)] into the multitarget framework of TCM and evaluating compound TCM formulas (not just monomers) via the Jun-Chen-Zuo-Shi principle, bridging traditional compatibility theory to modern network pharmacology. Addressing real-world barriers (bioavailability and quality control) and proposing actionable solutions (nanotechnology and randomized controlled trials (RCTs)].

PATHOLOGICAL MECHANISMS AND THERAPEUTIC STATUS OF MAJOR HLIDS

To contextualize the role of TCM, we summarize HLID pathophysiology and limitations of current therapies (Table 1).

Table 1 Summary of hereditary liver diseases pathophysiology and current therapies.

Disease	Genetic defect	Core pathology	Current therapies	Limitations
WD	ATP7B	Copper overload → ROS → apoptosis/fibrosis	Chelators (Dpenicillamin), zinc	Lifelong use; neurotoxicity
AATD	SERPINA1	Z-AAT aggregation → ER stress → fibrosis	AAT augmentation (lungs), transplantation	No liver-targeted therapy
HH	HFE	Hepcidin deficiency → iron overload → ferroptosis	Phlebotomy, chelators	Poor adherence; toxicity
GSD	Glycogen metabolism genes	Hypoglycemia → metabolic dysregulation	Dietary management	No cure; transplantation-dependent

WD: Wilson’s disease; AATD: 1-antitrypsin deficiency; HH: Hereditary hemochromatosis; GSD: Glycogen storage disease; ROS: Reactive oxygen species; ER: Endoplasmic reticulum.

Hepatolenticular degeneration (WD)

WD is an autosomal recessive disorder caused by ATP7B mutations, impairing hepatic copper export[18]. Excess copper generates reactive oxygen species (ROS) via the Fenton reaction, inducing hepatocyte apoptosis, fibrosis, and neurological damage (Kayser-Fleischer rings)[19]. First-line therapies (chelators and zinc) remove copper but fail to reverse neurodegeneration or correct genetic defects[20].

AATD

AATD arises from SERPINA1 mutations (e.g., Z-variant), causing misfolded AAT aggregation in the endoplasmic reticulum (ER), triggering ER stress, hepatocyte apoptosis, and fibrosis[21]. Lung damage results from low circulating functional AAT, enabling neutrophil elastase-mediated emphysema[22]. No therapies target Z-protein aggregation, and management is organ-specific (AAT augmentation for lungs, transplantation for end-stage liver disease)[23].

HH

HH is driven by HFE mutations, reducing hepcidin (the master iron regulator)[24]. Uncontrolled intestinal iron absorption leads to systemic overload - iron catalyzes ROS via the Fenton reaction, inducing ferroptosis (iron-dependent lipid peroxidation) and hepatocellular carcinoma[25]. Phlebotomy lowers iron stores but requires lifelong adherence; chelators have dose-limiting toxicity[26].

GSD

GSDs are autosomal recessive disorders of glycogen metabolism (e.g., GSD Ia: G6PC mutations), causing hypoglycemia, hepatomegaly, and metabolic complications (lactic acidosis and hyperlipidemia)[27]. Treatment is dietary (cornstarch supplementation), with liver transplantation reserved for end-stage disease[28].

Progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis caused by mutations in ATP8B1, ABCB11, or ABCB4, leads to defective bile transport and chronic cholestasis that predispose to intrahepatic stones[29]. Although typically pediatric, atypical cases may present in adults as an underlying HLID. Management often includes ursodeoxycholic acid (UDCA) to improve bile flow. While UDCA was historically sourced from bear bile in TCM, modern clinical practice uses synthetic UDCA, in line with ethical and conservation standards[30].

BIOACTIVE COMPONENTS OF TCM FOR HLIDS: CHEMISTRY AND SOURCES

The efficacy of TCM stems from chemically diverse bioactive components, each with distinct scaffolds and pharmacokinetics. We categorize key components by structural class and link their chemistry to HLID-relevant activities. We provide a disease specific evidence table (Table 2) that summarizes the component, disease/model, main outcomes, and level of evidence.

Table 2 Summary of disease-specific preclinical and clinical evidence for bioactive components of traditional Chinese medicine.

Component	Model	Main outcomes	Lever of evidence	Ref.
Berberine	In vitro (cell experiment)	Enhances clearance of aberrant proteins	Preclinical	Rusmini et al[74], 2020
		Directly chelates excess copper and iron ions	Preclinical	Purwaningsih et al[16], 2023
		Inhibits inflammatory response induced by LPS through NF-κB pathway	Preclinical	Reddi et al[93], 2021
		Inhibits ferroptosis	Preclinical	Wang et al[84], 2024
		Indirectly blocks the maturation of IL-1β/IL-18 and the cleavage of GSDMD	Preclinical	El Gazzar et al[92], 2025
	In vivo (animal experiment)	Attenuates fructose-induced insulin resistance in mice	Preclinical	Li et al[111], 2020
		Protects against diabetic retinopathy in mice	Preclinical	Zhai et al[136], 2020
		Significantly improves the composition of intestinal microbiota, increases beneficial bacteria, and inhibits opportunistic pathogens	Preclinical	Dehau et al[126], 2023
		Inhibits osteosarcoma	Preclinical
	Clinical trial/meta-analysis	Efficacy and safety for premature ventricular contractions	Metaanalysis of randomized controlled trials (level 1a evidence)	Qiao et al[34], 2023
Matrine	In vitro (cell experiment)	Indirectly blocks the maturation of IL-1β/IL-18 and the cleavage of GSDMD	Preclinical	Sun et al[91], 2025
		Suppresses the production of core pro-inflammatory cytokines (TNF-α, IL-6)	Preclinical	Sun et al[94], 2019
	In vivo (animal experiment)	Inhibits IL-1β secretion in primary porcine alveolar macrophages	Preclinical	Sun et al[94], 2019
		Potential for multi-targeted intervention in hereditary liver diseases	Preclinical	Sun et al[33], 2022
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Quercetin	In vitro (cell experiment)	Directly scavenges free radicals	Preclinical	Afanas'ev et al[65], 1989
		Directly interacts with misfolded proteins to inhibit their aggregation	Preclinical	Alghamdi et al[75], 2022
		Protects ethanol-induced hepatocyte pyroptosis	Preclinical	Zhao et al[123], 2022
		Acts as a potent antioxidant	Preclinical	Aghababaei and Hadidi[79], 2023
		Suppresses the production of core pro-inflammatory cytokines (TNF-α, IL-6)	Preclinical	Li et al[95], 2021
		As a direct antioxidant	Preclinical	Remigante et al[110], 2022
	In vivo (animal experiment)	Attenuates the activation of hepatic stellate cells and liver fibrosis in mice	Preclinical	Li et al[132], 2016
		Inhibits hepatic gluconeogenesis in diabetic rats	Preclinical	Chen et al[115], 2020
		Modulates T-cell homeostasis	Preclinical	Ke et al[105], 2023
		Regulates the expression of genes associated with hepatic lipid metabolism	Preclinical	Luo et al[155], 2025
		Antidiabetic effects in diabetic rats (in vivo and in silico studies)	Preclinical	Abdou et al[114], 2025
		Fabrication and in vitro/vivo evaluation of quercetin nanocrystals for liver targeted drug delivery	Preclinical	Shen et al[38], 2024
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Baicalin	In vitro (cell experiment)	Directly scavenges free radicals	Preclinical	Liang et al[66], 2009
		Interferes with the IRE1α/TRAF2/JNK pathway	Preclinical	Hao et al[69], 2021
		Acts as a potent antioxidant	Preclinical	Zhao et al[82], 2020
		Indirectly blocks the maturation of IL-1β/IL-18 and the cleavage of GSDMD	Preclinical	Rui et al[90], 2020; Song et al[102], 2025
		Suppresses the production of core pro-inflammatory cytokines (TNF-α, IL-6)	Preclinical	He et al[96], 2022
		Inhibits HSC proliferation, apoptosis, invasion, migration, and activation	Preclinical	Wu et al[138], 2018
	In vivo (animal experiment)	Ameliorates experimental liver cholestasis in mice	Preclinical	Shen et al[41], 2017
		Inhibited CYP7A1 expression, improved bile acid, and glycolipid metabolism in T2DM mice	Preclinical	Yan et al[131], 2022
		Ameliorates atherosclerosis in apolipoprotein E-deficient mice	Preclinical	Zhao et al[82], 2020
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Ursolic acid	In vitro (cell experiment)	Enhances the expression of endogenous antioxidant enzyme systems	Preclinical	Fu et al[45], 2023
		Exerts ferroptosis-defensive effects	Preclinical	Fu et al[45], 2023
	In vivo (animal experiment)	Reduces oxidative stress injury to ameliorate experimental autoimmune myocarditis in mice	Preclinical	Fu et al[45], 2023
		Ameliorates hepatic steatosis and improves metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats	Preclinical	Li et al[118], 2014
		Activates Nrf2, an endogenous defense hub	Preclinical	Wang et al[106], 2023; Bak et al[108], 2017
		Suppresses TGF-β1-induced quiescent HSC activation and transformation	Preclinical	Yu et al[140], 2017
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Oleanolic acid	In vitro (cell experiment)	Exerts ferroptosis-defensive effects	Preclinical	Wang et al[87], 2025
	In vivo (animal experiment)	Alleviates TNBS-induced ulcerative colitis in rat	Preclinical	Wang et al[87], 2025
		Hepatoprotection	Preclinical	Wang et al[46], 2018
		Activates the peroxisome proliferator-activated receptor α signaling pathway	Preclinical	Wang et al[46], 2018
		Activates Nrf2, an endogenous defense hub	Preclinical	Bojuan et al[107], 2025; Bak et al[108], 2017
		Attenuates activation of hepatic stellate cells	Preclinical	Leilei et al[141], 2022
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Astragalus polysaccharide	In vitro (cell experiment)	Alleviates ERS	Preclinical	Wang et al[71], 2009
		Enhances the expression of endogenous antioxidant enzyme systems	Preclinical	Sha et al[64], 2023
		Inhibits the activation of the NLRP3 inflammasome	Preclinical	Tian et al[98], 2017
	In vivo (animal experiment)	Upregulates hepcidin expression and reduces iron overload in mice	Preclinical	Ren et al[48], 2016
		Improves insulin sensitivity in 3T3-L1 adipocytes	Preclinical	Zhang et al[112], 2018
		Mitigates transport stress-induced hepatic metabolic stress in chicks	Preclinical	Zhao et al[125], 2022
		Significantly improves the composition of intestinal microbiota, increases beneficial bacteria, and inhibits opportunistic pathogens	Preclinical	Zhao et al[127], 2023
		Attenuates murine colitis	Preclinical	Tian et al[98], 2017
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Ganoderma lucidum polysaccharide	In vitro (cell experiment)	May exert effects through direct or indirect mechanisms to inhibit misfolded protein aggregation	Preclinical	Zeng et al[76], 2017
	In vivo (animal experiment)	Improves rat DSS-induced colitis	Preclinical	Xie et al[128], 2019
		Anti-inflammatory and hepatoprotective effects against carbon tetrachloride-induced liver injury in Kunming Mice	Preclinical	Chen et al[99], 2019
		Inhibits the activation of the NLRP3 inflammasome	Preclinical	Chen et al[99], 2019
		Indirectly maintains metabolic homeostasis	Preclinical	Pan et al[124], 2021
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Ginsenoside Rg1	In vitro (cell experiment)	Interferes with the IRE1α/TRAF2/JNK pathway	Preclinical	Li et al[70], 2017
		Acts as a potent antioxidant	Preclinical	Li et al[83], 2021
	In vivo (animal experiment)	Protects cardiomyocytes against hypoxia/reoxygenation injury	Preclinical	Li et al[70], 2017
		Inhibits dietary-induced obesity and improves obesity-related glucose metabolic disorders	Preclinical	Li et al[113], 2018
		Inhibits inflammatory responses in alcoholic hepatitis	Preclinical	Li et al[134], 2018
		Ameliorates cardiac oxidative stress and inflammation in streptozotocin-induced diabetic rats	Preclinical	Qin et al[121], 2019
		Ameliorates aging-induced liver fibrosis in SAMP8 mice	Preclinical	Li et al[83], 2021
		Regulates the polarization of macrophages from M1 to M2 phenotype	Preclinical	Zhen et al[103], 2024
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Saikosaponin	In vitro (cell experiment)	No specific in vitro evidence for hereditary liver diseases mentioned in the provided text	Preclinical
	In vivo (animal experiment)	Inhibits the activation of the NLRP3 inflammasome	Preclinical	Lin et al[100], 2018
		Inhibits peritoneal fibrosis in rats with renal failure	Preclinical	Ruiqi et al[142], 2021
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Salvianolic acid B	In vitro (cell experiment)	Directly chelates excess copper and iron ions	Preclinical	Xie et al[17], 2025
		Modulates the PERK/eIF2α/CHOP signaling axis	Preclinical	Mai et al[68], 2020
		Acts as a potent antioxidant	Preclinical	Wu et al[81], 2009
		As a direct antioxidant	Preclinical	Xiao et al[109], 2020
	In vivo (animal experiment)	Protects against acute and chronic liver injury	Preclinical	Tao et al[133], 2021
		Protects the integrity of mitochondrial membrane potential	Preclinical	Zheng et al[122], 2020
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Resveratrol	In vitro (cell experiment)	Modulates the PERK/eIF2α/CHOP signaling axis	Preclinical	Liu et al[67], 2014
		Upregulates the expression of glutathione peroxidase 4	Preclinical	Ni et al[86], 2023
		Acts as a potent antioxidant	Preclinical	Liu et al[80], 2022
		Regulates lipid metabolism in hepatocytes	Preclinical	Wang et al[117], 2024
	In vivo (animal experiment)	Attenuates myocardial injury	Preclinical	Liu et al[80], 2022
		Accelerates wound healing in diabetic mice	Preclinical	Ding et al[104], 2022
		Enhances mitochondrial biogenesis and improves ATP production efficiency	Preclinical	Zhang et al[62], 2017
		Alleviates intestinal mucosal barrier dysfunction in dextran sulfate sodium-induced colitis mice	Preclinical	Pan et al[130], 2020
		Synergistic antitumorigenic activity with calcitriol in triple negative breast cancer xenografts	Mediated by angiogenesis inhibition	García-Quiroz et al[150], 2019
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text
Curcumin	In vitro (cell experiment)	Enhances the clearance of aberrant proteins	Preclinical	Liu et al[72], 2023; Zhang et al[73], 2016
		Effectively inhibits the activation of the NLRP3 inflammasome	Preclinical	Sun et al[89], 2017
		Acts as a potent antioxidant	Preclinical	Xiong et al[78], 2025
		Upregulates the expression of glutathione peroxidase 4	Preclinical	Yuan et al[85], 2023
		Suppresses the production of core pro-inflammatory cytokines (TNF-α, IL-6)	Preclinical	Kong et al[97], 2025
		Inhibits the activation of the NLRP3 inflammasome	Preclinical	Kong et al[101], 2016
		Significantly reduces lipid synthesis and accumulation in the liver	Preclinical	Tung et al[116], 2017
	In vivo (animal experiment)	Restrains oxidative stress after intracerebral hemorrhage in rat	Preclinical	Duan et al[63], 2022
		Protects against the intestinal ischemia-reperfusion injury	Preclinical	Tian et al[129], 2016
		Downregulates the expression of TGF-β1	Preclinical	Song et al[139], 2011
		Synergistic hepatoprotective activity with rosemary essential oil	Preclinical	Mahmoudi et al[151], 2022
		Comparison of the efficacy of curcumin and its nano formulation on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in Wistar rats	Preclinical	Hamed et al[159], 2024
	Clinical trial/meta-analysis	No specific clinical trial or meta-analysis evidence for hereditary liver diseases mentioned in the provided text

LPS: Lipopolysaccharide; NF-κB: Nuclear factor-κB; IL: Interleukin; GSDMD: Gasdermin D; TNF-α: Tumor necrosis factor-α; HSC: Hepatic stellate cell; Nrf2: Nuclear factor erythroid 2-related factor 2; TGF-β1: Transforming growth factor β1; ERS: Endoplasmic reticulum stress; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; DSS: Dextran sulfate sodium.

Alkaloids: Berberine and matrine

Alkaloids are a class of nitrogen-containing basic organic compounds[31] and represent the core bioactive components of many TCMs. Among them, berberine and matrine have demonstrated potential for multitargeted intervention in the therapeutic exploration for HLIDs[32,33]. Chemical structures of berberine and matrine are shown in Figure 1. Berberine (isoquinoline alkaloid, quaternary ammonium structure) from Coptis chinensis and Phellodendron amurense chelates copper/iron and activates AMP-activated protein kinase (AMPK)[34]. Matrine (quinolizidine alkaloid, tetracyclic structure) from Sophora flavescens inhibits NLRP3 inflammasomes and autophagy[35].

Figure 1  Chemical structures of berberine, matrine, quercetin, baicalin, ursolic acid, oleanolic acid, ginsenoside Rg1, saikosaponin, salvianolic acid B, resveratrol, and curcumin.

Flavonoids: Quercetin and baicalin

Flavonoids are a class of polyphenolic compounds widely distributed in plants, with diverse biological activities[36]. Based on structural differences, they are classified into subclasses such as flavones, flavonols, isoflavones, flavanones, and anthocyanins[37]. Quercetin and baicalin exhibit therapeutic potential for HLIDs[38,39]. Chemical structures of quercetin and baicalin are shown in Figure 1. Quercetin (flavonol, pentahydroxy substitution) from Panax notoginseng and Morus alba scavenges free radicals and modulates metal ion homeostasis[40]. Baicalin (flavone glycoside) from Scutellaria baicalensis inhibits ER stress and transforming growth factor (TGF)-β1-mediated fibrosis[41].

Terpenoids: Ursolic acid and oleanolic acid

Ursolic acid (UA) and oleanolic acid (OA), two structural isomers belonging to pentacyclic triterpenoids[42], have garnered considerable attention for their significant therapeutic potential in HLIDs, attributed to their multitarget pharmacological properties such as antioxidative stress, anti-inflammation, and anti-hepatic fibrosis[43]. Chemical structures of UA and OA are shown in Figure 1. As a ursane-type pentacyclic triterpene, UA is structurally characterized by an angular methyl group at the C-29 position and a geminal dimethyl group at the C-19/C-30 positions on the E-ring[44]. UA (ursane-type pentacyclic triterpenoid) from Ligustrum lucidum activates Nrf2 and inhibits ferroptosis[45]. OA (oleanane-type isomer) from Olea europaea modulates peroxisome proliferator-activated receptor α for lipid clearance[46].

Polysaccharides: Astragalus polysaccharide and Ganoderma lucidum polysaccharide

Polysaccharides are high-molecular-weight compounds formed by the polymerization of > 10 monosaccharide units via glycosidic linkages, with ubiquitous distribution in plants, fungi, and algae[47]. As a member of α-glucans, Astragalus polysaccharide (APS) is structurally characterized by a glucose backbone linked through α-(1 → 4) glycosidic bonds, with branched chains attached at the 6-O positions. This unique spatial configuration endows it with excellent water solubility and immunomodulatory properties. APS (α-glucan from Astragalus membranaceus) upregulates hepcidin via p38 MAPK and modulates the gut microbiota[48]. Glucagon-like peptide (β-glucan from Ganoderma lucidum) enhances antioxidant capacity and macrophage polarization[49].

Saponins: Ginsenoside Rg1 and saikosaponin

Saponins are natural compounds constituted by covalent linkage of aglycones to sugar chains via glycosidic bonds[50]. Based on aglycone structural diversity, they are taxonomically categorized into two major classes: Triterpenoid and steroidal saponins[51]. Chemical structures of ginsenoside Rg1 and saikosaponin are shown in Figure 1. Rg1 belongs to dammarane-type tetracyclic triterpenoids, using protopanaxatriol as its aglycone. Structurally, it bears glucose moieties at the C-6 and C-20 positions, respectively[52,53]. This unique glycosylation pattern confers excellent water solubility, a prerequisite for biological bioavailability, and underpins its diverse bioactivities[54]. Rg1 (dammarane-type triterpenoid saponin) from Panax ginseng inhibits nuclear factor (NF)-κB and promotes M2 macrophage polarization[52]. Saikosaponins are oleanane-type pentacyclic triterpenoids, characterized by a multiglycosyl chain linked to the aglycone C-3 position[55]. Among saikosaponin subtypes, saikosaponin A and saikosaponin D serve as the principal bioactive components, and the acetylation pattern of the terminal sugar chain, as a pivotal regulatory factor, modulates their bioactivity by governing key pharmacological processes, including signal pathway transduction[56]. Saikosaponin (oleanane-type, e.g., Saikosaponin D) from Bupleurum chinense suppresses TGF-β/Smad-mediated fibrosis[57].

Polyphenols: SalB, resveratrol, and curcumin

Polyphenols are a class of aromatic natural compounds characterized by multiple phenolic hydroxyl groups, and they can be categorized into flavonoids, phenolic acids, stilbenes, tannins, diarylheptanoids, and other subclasses based on their core skeleton structures[58]. Chemical structures of SalB, resveratrol, and curcumin are shown in Figure 1. SalB is structurally formed by condensation of three danshensu molecules and one caffeic acid molecule via ester bonds[59]. Resveratrol, a member of the stilbene subclass, is structurally featured by a 1,2-diphenylethylene scaffold, with two benzene rings linked by a vinyl bridge and hydroxyl substitutions at the 3, 5, and 4’ positions of the benzene rings[60]. Curcumin, a linear diarylheptanoid polyphenol, possesses a core structure consisting of two O-methoxyphenol rings connected by a seven-carbon chain, which comprises a set of α,β-unsaturated β-diketone structural units[61]. SalB (phenolic acid dimer from Salvia miltiorrhiza) chelates iron and inhibits ferroptosis[59]. Resveratrol (stilbene from Polygonum cuspidatum) activates sirtuin 1 and modulates mitochondrial function[62]. Curcumin (diarylheptanoid from Curcuma longa) inhibits NLRP3 and autophagy[63]. Curcumin can exert dual regulatory effects on autophagy depending on cellular context, dosage, and disease stage.

MECHANISMS OF ACTION: FROM MOLECULES TO PATHWAYS

The multitarget effects of TCM converge on the following seven core HLID pathogenic pathways. Rather than acting in isolation, TCM components engage in synergistic interactions that construct a multitarget regulatory network. These observations provide a plausible mechanistic insight into HLID pathogenesis. Importantly, the schematic depicts TCM-centered pharmacological actions, not a shared disease-specific pathology.

Metal ion homeostasis and oxidative stress regulation

Bioactive components of TCM have demonstrated a comprehensive therapeutic strategy in regulating metal ion homeostasis and antagonizing oxidative damage in HLIDs, via a multitargeted and multilayered mode of action (Figure 2). Certain metabolic HLIDs (e.g., WD, hemochromatosis) are associated with abnormal copper or iron handling, which could exacerbate hepatobiliary injury and create a permissive environment for intrahepatic stone formation, whereas other HLIDs are unrelated to metal accumulation. TCM components restore homeostasis via dual mechanisms: Berberine binds Cu²⁺/Fe²⁺, facilitating biliary/excretory clearance[16]; SalB forms stable complexes with iron, reducing Fenton-reaction-driven ROS[17]. APS activates p38 MAPK to increase hepcidin expression, reducing intestinal iron absorption at the source[48].

Figure 2 Mechanisms of metal ion homeostasis regulation and oxidative damage antagonism by traditional Chinese medicine bioactive components in hepatolithiasis-inducing liver diseases. A: Iron homeostasis: Excessive iron accumulation exacerbates hepatobiliary injury in hepatolithiasis-inducing liver diseases (e.g., hereditary hemochromatosis). Berberine and salvianolic acid B directly chelate Fe³⁺/Fe²⁺, reducing the labile iron pool and suppressing Fenton reactions. Astragalus polysaccharide activates the p38 mitogen-activated protein kinase pathway, upregulating hepcidin, which degrades the iron exporter ferroportin to limit systemic iron overload; B: Oxidative damage antagonism: Traditional Chinese medicine components mitigate reactive oxygen species-driven biliary epithelial injury through complementary mechanisms: Curcumin, Astragalus polysaccharide, and ursolic acid activate nuclear factor erythroid 2-related factor 2, inducing antioxidant enzymes (superoxide dismutase, catalase) via the antioxidant response element pathway; quercetin and β-carotene directly scavenge free radicals and inhibit lipid peroxidation; baicalin and salvianolic acid B combine direct reactive oxygen species scavenging with iron chelation to block Fenton-mediated hydroxyl radical generation. MAPK: Mitogen-activated protein kinase; Nrf2: Nuclear factor erythroid 2-related factor 2; ARE: Antioxidant response element; SOD: Superoxide dismutase; CAT: Catalase; ROS: Reactive oxygen species.

For oxidative stress, components enhance endogenous defenses: Curcumin, APS, and UA activate Nrf2 (master antioxidant regulator), upregulating superoxide dismutase, catalase, and glutathione peroxidase[63,64]. Quercetin and baicalin directly scavenge ROS via phenolic hydroxyl groups[65,66], framed as a protective response against oxidative biliary injury, which reduces ductal epithelial damage and limits the initiation of stone-forming nidi.

Inhibition of abnormal protein aggregation and ER stress

The active ingredients derived from TCM use a multitarget and multilevel synergistic strategy, providing a systemic therapeutic approach for HLIDs by targeting the core pathologies of aberrant protein aggregation and alleviating ER stress (Figure 3). In regulating the core ER stress pathways, these components act through multiple mechanisms: Resveratrol[67] and SalB[68] modulate the PERK/eIF2α/CHOP signaling axis, thereby suppressing ER stress-mediated apoptosis; baicalin[69] and Rg1[70] interfere with the IRE1α/TRAF2/JNK pathway, mitigating inflammatory responses and promoting hepatocyte survival; and APS[71] alleviates ERS by inhibiting the excessive activation of the ATF6 pathway and reducing the expression of downstream detrimental factors such as protein tyrosine phosphatase 1B. Regarding the management of misfolded proteins, the ingredients form a collaborative network: Curcumin[72,73] and berberine[74] enhance the clearance of aberrant proteins by activating the autophagy-lysosomal pathway; quercetin[75] directly interacts with misfolded proteins to inhibit their aggregation; and Ganoderma lucidum polysaccharide (GLP)[76] may exert similar effects through direct or indirect mechanisms.

Figure 3 Modulation of endoplasmic reticulum stress and protein homeostasis by bioactive components of traditional Chinese medicine in hereditary liver disease. This schematic illustrates how traditional Chinese medicine-derived compounds (resveratrol, baicalin, curcumin, berberine, quercetin) target core proteostatic pathways disrupted in genetic hepatopathies (e.g., α₁-antitrypsin deficiency, ABC transporter misfolding in progressive familial intrahepatic cholestasis). These compounds converge on endoplasmic reticulum stress mitigation, autophagic enhancement, and hepatoprotection, highlighting actionable therapeutic targets for restoring hepatic proteostasis in hereditary liver disease. Four color-coded modules define the mechanisms: Orange, antioxidant defense and inhibition of endoplasmic reticulum/reactive oxygen species-mediated apoptosis via sirtuin 1 activation and glutathione restoration. Purple, rebalancing of the unfolded protein response through attenuation of the PERK-CHOP axis and preservation of BiP/GRP78 chaperone capacity. Green, restoration of autophagy-lysosome flux via mTORC1 inhibition and TFEB-mediated lysosomal biogenesis. Blue, promotion of misfolded protein clearance through proteasomal degradation and suppression of toxic aggregate formation. Solid arrows denote activation; T-bars indicate inhibition. SIRT1: Sirtuin 1; ER: Endoplasmic reticulum; Nrf2: Nuclear factor erythroid 2-related factor 2; ROS: Reactive oxygen species; HO-1: Heme oxygenase-1; JNK: C-Jun n-terminal kinase; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin.

Regulation of nonapoptotic cell death: Ferroptosis and pyroptosis

Bioactive components of TCM could ameliorate HLIDs by targeting ferroptosis and pyroptosis; two nonapoptotic forms of regulated cell death (Figure 4). Regarding ferroptosis, a process driven by iron-dependent lipid peroxidation[77], curcumin[78], quercetin[79], resveratrol[80], SalB[81], baicalin[82], Rg1[83], and berberine[84] primarily act as potent antioxidants, directly scavenging lipid free radicals or enhancing the overall antioxidant capacity of cells. Curcumin[85] and resveratrol[86] can upregulate expression of glutathione peroxidase 4; a key anti-lipid peroxidation enzyme. UA[45] and OA[87] exert ferroptosis-defensive effects by activating the Nrf2 signaling pathway. For pyroptosis, an inflammatory form of cell death mediated by gasdermin (GSDM) D pore formation[88], curcumin[89] effectively inhibits the activation of the NLRP3 inflammasome, preventing the cleavage of pro-caspase-1 into its active form. Baicalin[90], matrine[91], and berberine[92] indirectly block the maturation of interleukin (IL)-1β/IL-18 and the cleavage of GSDMD mainly through inhibiting the NLRP3 inflammasome or downregulating caspase-1 expression. Inhibition of the NLRP3 inflammasome by baicalin, matrine, and berberine is contextualized as a means to suppress sterile inflammation, decrease IL-1β/IL-18-mediated tissue injury, and attenuate GSDMD-driven pyroptosis, all of which contribute to chronic biliary inflammation and stone progression.

Figure 4 Dual modulation of ferroptosis and pyroptosis by natural bioactive compounds. This schematic illustrates how traditional Chinese medicine-derived compounds concurrently suppress ferroptotic and pyroptotic cell death, two major pathological drivers in inflammatory and degenerative diseases. The diagram is organized into two interconnected pathways: (1) Ferroptosis suppression (upper panel): Reactive oxygen species-induced lipid peroxidation (LOO•) and iron (Fe²⁺) accumulation are central to ferroptosis. Traditional Chinese medicine compounds such as curcumin, quercetin, resveratrol, salvianolic acid B, baicalin, ginsenoside Rg1, and berberine inhibit lipid peroxidation chain reactions and chelate iron, thereby reducing cytotoxic aldehydes (LOOH) and promoting membrane repair. Ursolic acid and oleanolic acid activate the nuclear factor erythroid 2-related factor 2 transcription factor in the nucleus, enhancing expression of antioxidant genes including glutathione peroxidase 4, which reduces LOOH to non-toxic LOH, further protecting membrane integrity; and (2) Pyroptosis suppression (lower panel): Danger signals activate the NOD-, LRR- and pyrin domain-containing protein 3 inflammasome, triggering caspase-1 activation, which cleaves gasdermin D (GSDMD) into its pore-forming N-terminal fragment (GSDMD-N) and pro-inflammatory cytokines [pro-interleukin (IL)-1β/pro-IL-18] into mature IL-1β/IL-18. Curcumin, baicalin, matrine, and berberine disrupt this cascade by inhibiting NOD-, LRR- and pyrin domain-containing protein 3 assembly and/or caspase-1 activity, thereby preventing GSDMD pore formation, cell lysis, and release of pro-inflammatory cytokines. IL: Interleukin; GPX4: Glutathione peroxidase 4; Nrf2: Nuclear factor erythroid 2-related factor 2; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; GSDMD: Gasdermin D.

Immune and inflammatory microenvironment remodeling

Bioactive components of TCM construct a three-dimensional regulatory network for improving HLIDs by multidimensionally and synergistically modulating the immune and inflammatory microenvironment (Figure 5). At the molecular level, berberine[93], matrine[94], quercetin[95], baicalin[96], and curcumin[97] suppress the production of core proinflammatory cytokines such as tumor necrosis factor-α and IL-6 through inhibiting the NF-κB signaling pathway. APS[98], GLP[99], saikosaponin[100], and curcumin[101] inhibit the activation of the NLRP3 inflammasome, and act synergistically with baicalin[102], matrine, and berberine to block the activity of caspase-1, thereby suppressing pyroptosis and the mature release of IL-1β/IL-18. At the cellular level, ginsenoside Rg1[103] and resveratrol[104] regulate the polarization of macrophages from the M1 to M2 phenotype, while quercetin[105] modulates T-cell homeostasis, collectively remodeling an immune microenvironment conducive to tissue repair. UA[106] and OA[107] activate Nrf2, an endogenous defense hub, which induces expression of antioxidant genes such as HO-1 and NQO1, and their products can directly inhibit NF-κB activity[108], forming a robust negative feedback regulatory loop that alleviates oxidative-stress-driven inflammation at its source. In contrast, SalB[109] and quercetin[110], as direct antioxidants, scavenge ROS to break the vicious cycle between oxidative stress and inflammation.

Figure 5 Regulation of immune and inflammatory microenvironment by traditional Chinese medicine bioactive components. This schematic delineates the multi-targeted immunomodulatory and anti-inflammatory mechanisms of traditional Chinese medicine-derived compounds, focusing on their actions against nuclear factor-κB-driven inflammation, macrophage polarization, T-cell homeostasis, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis, and oxidative stress. Compounds such as berberine, matrine, quercetin, baicalin, and curcumin suppress nuclear factor-κB nuclear translocation and subsequent production of pro-inflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6. Ginsenoside Rg1 and resveratrol promote the transition from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages, while salvianolic acid B and quercetin further support this repolarization. Quercetin restores the balance between regulatory Treg cells and pro-inflammatory Th17 cells. Ursolic acid and oleanolic acid activate nuclear factor erythroid 2-related factor 2, conferring antioxidative and anti-inflammatory effects. Danger signals activate the NLRP3 inflammasome, triggering caspase-1-mediated cleavage of gasdermin D into its pore-forming gasdermin D-N fragment, leading to IL-1β/IL-18 maturation and pyroptotic cell lysis. Compounds such as Astragalus polysaccharide, ganoderma lucidum polysaccharide, saikosaponin, curcumin, baicalin, matrine, and berberine block NLRP3 assembly or downstream steps, thereby attenuating pyroptosis. TNF-α: Tumor necrosis factor-α; IL: Interleukin; Nrf2: Nuclear factor erythroid 2-related factor 2; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; GSDMD: Gasdermin D.

Metabolic reprogramming

Bioactive components of TCM play a pivotal role in the treatment of HLIDs by intervening in metabolic reprogramming (Figure 6). In terms of glucose metabolism regulation, berberine[111], APS[112], and ginsenoside Rg1[113] activate the AMPK signaling pathway, promote glucose uptake and glycogen synthesis, and ameliorate insulin resistance. Quercetin inhibits the transcription of hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase to reduce gluconeogenesis by activating liver kinase B1-AMPKα and improving the phosphatidylinositol 3-kinase-protein kinase B-forkhead box protein O1 signaling pathway to promote the phosphorylated inactivation of forkhead box O1[114,115]. At the level of lipid metabolism regulation, curcumin, and baicalin can significantly reduce lipid synthesis and accumulation in the liver by inhibiting the expression of sterol regulatory element-binding protein-1c, a key transcription factor in lipid synthesis, and its downstream target genes[116]. Resveratrol regulates lipid metabolism in hepatocytes by activating the AMPK signaling pathway[117]. UA[118] and OA[46] activate the peroxisome proliferator-activated receptor α signaling pathway, promote fatty acid β-oxidation, and accelerate lipid clearance. Quercetin[119] and saponins[120] regulate the expression of genes associated with hepatic lipid metabolism, thereby ameliorating dysregulated lipid metabolism. Ginsenoside Rg1[121] and resveratrol[62] enhance mitochondrial biogenesis and improve ATP production efficiency. SalB[122] and quercetin[123] protect the integrity of mitochondrial membrane potential, alleviating mitochondrial dysfunction induced by metabolic stress. GLP[124] and APS[125] indirectly maintain metabolic homeostasis by improving the energy metabolism status of hepatocytes.

Figure 6 Modulation of glucose metabolism, lipid metabolism, and mitochondrial function by traditional Chinese medicine bioactive components. This schematic illustrates the multitargeted metabolic regulatory mechanisms of traditional Chinese medicine-derived compounds across three interconnected pathways: Glucose metabolism, lipid metabolism, and mitochondrial energy homeostasis, highlighting their potential in managing metabolic disorders and liver diseases. Berberine, Astragalus polysaccharide, and Ginsenoside Rg1 activate activated protein kinase (AMPK) signaling, enhancing glucose uptake and glycogen synthesis. Quercetin suppresses gluconeogenesis via the LKB1-AMPK and phosphatidylinositol 3-kinase-protein kinase B-forkhead box protein O1 pathways, reducing hepatic glucose output. Curcumin and baicalin inhibit SREBP-1c-driven fatty acid synthesis (via ACC/FAS downregulation); resveratrol activates AMPK to suppress lipogenesis; ursolic acid and oleanolic acid activate peroxisome proliferator-activated receptor α to promote fatty acid β-oxidation; quercetin and saponins regulate lipid metabolism gene networks. Ginsenoside Rg1 and resveratrol enhance mitochondrial membrane potential (ΔΨm), supporting bioenergetics. Quercetin, salvianolic acid B, and Astragalus polysaccharide improve cellular energy metabolism status, likely via mitochondrial quality control and oxidative phosphorylation optimization. AMPK: Activated protein kinase; PI3K: Phosphatidylinositol 3 kinase; Akt: Protein kinase B; FOXO1: Forkhead box protein O1; PPARα: Peroxisome proliferator-activated receptor α.

Gut-liver axis modulation

Bioactive components of TCM exert therapeutic effects on HLIDs by regulating the gut-liver axis (Figure 7). In terms of gut microbiota modulation, berberine[126], APS[127], and GLP[128] significantly improve the composition of intestinal microbiota, increase the abundance of beneficial bacteria, and inhibit the growth of opportunistic pathogens. Curcumin[129] and resveratrol[130] enhance the expression of intestinal tight junction proteins, thereby improving intestinal barrier function. At the level of bile acid metabolism regulation, baicalin[131] inhibits cytochrome P450 family 7 subfamily A member 1 by upregulating the hepatic FXR-SHP pathway to maintain bile acid homeostasis.

Figure 7 Modulation of gut microbiota & intestinal barrier and hepatic bile acid metabolism by traditional Chinese medicine bioactive components. This schematic depicts the crosstalk between gut microbiota modulation, intestinal barrier integrity, and hepatic bile acid homeostasis regulated by traditional Chinese medicine-derived compounds, emphasizing their therapeutic potential in metabolic and cholestatic liver diseases. Berberine, Astragalus polysaccharide, and Ganoderma lucidum polysaccharide promote the proliferation of beneficial bacteria (Lactobacillus, Bifidobacterium) while suppressing opportunistic pathogens. Curcumin and resveratrol enhance intestinal epithelial tight junction integrity, reducing intestinal permeability and subsequent endotoxin influx. Baicalin modulates hepatic bile acid synthesis and transport via the nuclear receptor farnesoid X receptor, which upregulates small heterodimer partner and inhibits CYP7A1 (the rate-limiting enzyme in bile acid synthesis). This mechanism reduces bile acid overload in hepatocytes, mitigating cholestatic injury and improving liver function. FXR: Farnesoid X receptor; SHP: Small heterodimer partner.

Antihepatic fibrosis: Targeting hepatic stellate cell activation and EMT

Bioactive components of TCM exert multilayered regulatory effects on the fibrotic progression of HLIDs by targeting hepatic stellate cell (HSC) activation and EMT (Figure 8). In terms of inhibiting HSC activation, quercetin[132], baicalin[41], SalB[133], ginsenoside Rg1[134], resveratrol[135], berberine[136], and matrine[137] exhibit potent antioxidant and anti-inflammatory activities by scavenging ROS and regulating signaling pathways such as Nrf2 and NF-κB, indirectly attenuating the driving factors of HSC activation. Baicalin[138] inhibits HSC proliferation, apoptosis, invasion, migration, and activation through the miR-3595/ACSL4 axis. Curcumin[139] and resveratrol[72] can downregulate expression of TGF-β1, a key profibrotic cytokine, to inhibit the transduction of fibrotic signals. Regarding the direct regulation of HSC phenotype, UA[140] and OA[141] inhibit the TGF-β/Smad signaling pathway and reduce expression of activation markers such as α-smooth muscle actin, thus arresting the transdifferentiation of HSCs into myofibroblasts and EMT. Saikosaponin exerts antifibrotic effects through their holistic hepatoprotective and immunomodulatory functions[116,142].

Figure 8 Multifaceted mechanisms of traditional Chinese medicine bioactive components in inhibiting hepatic stellate cell activation and extracellular matrix remodeling. This schematic illustrates the dual-targeted anti-fibrotic strategies employed by traditional Chinese medicine-derived compounds, focusing on the attenuation of hepatic stellate cell (HSC) activation and the reversal of epithelial-mesenchymal transition, critical processes in liver fibrosis. In injured livers, damaged hepatocytes release reactive oxygen species and transforming growth factor-β1, triggering HSC proliferation, migration, and activation. Quercetin, baicalin, salvianolic acid B, ginsenoside Rg1, resveratrol, berberine, matrine, and curcumin counteract this by activating the nuclear factor erythroid 2-related factor 2 pathway (enhancing antioxidant defenses) and suppressing the nuclear factor-κB pathway (reducing pro-inflammatory gene expression). Baicalin and ACSL4/miR-3595 axis modulate HSC activation and fibrogenic signaling. Ursolic acid and oleanolic acid directly target activated HSCs/myofibroblasts, inhibiting the transforming growth factor-β1/Smad2/3/4 signaling cascade. This prevents the phosphorylation of Smad2/3, thereby preserving the epithelial phenotype (E-cadherin, cytokeratin) and suppressing the mesenchymal markers (vimentin, N-cadherin) and pro-fibrotic gene transcription. Consequently, the secretion of extracellular matrix (e.g., collagen, fibronectin) is attenuated. HSC: Hepatic stellate cell; ROS: Reactive oxygen species; TGF-β1: Transforming growth factor β1; EMT: Epithelial-mesenchymal transition; ECM: Extracellular matrix.

COMPOUND TCM: SYSTEMIC INTERVENTION VIA JUN-CHEN-ZUO-SHI COMPATIBILITY

Based on the compatibility principle of Jun-Chen-Zuo-Shi (sovereign-minister-assistant-messenger), compound TCM forms a synergistic therapeutic system, demonstrating the advantage of holistic regulation with multiple targets and pathways in the intervention of complex diseases[143].

Gandouling Decoction

Compound TCM formulations demonstrate a core pharmacological advantage through the principle of Jun-Chen-Zuo-Shi (sovereign-minister-assistant-messenger) compatibility; a succinct yet profound philosophy of intervention. In the management of complex diseases such as HLIDs, single-target agents often yield suboptimal outcomes. In contrast, compound TCM prescriptions, exemplified by Gandouling Decoction and Huangpu Tongqiao Capsule, establish synergistic therapeutic networks capable of multipathway modulation.

Gandouling Decoction[144], a classical formula used in treating hepatolenticular degeneration, comprises Rheum palmatum L., Coptis chinensis Franch, Curcuma longa L., Lysimachia christinae Hance, Alisma plantago-aquatica L., and Panax notoginseng (Aralia quinquefolia var. notoginseng Burkill). According to TCM theory, its herbs are assigned as follows based on the sovereign-minister-assistant-messenger (Jun-Chen-Zuo-Shi) principle: Sovereign (Jun): Rheum palmatum; Minister (Chen): Coptis chinensis and Lysimachia christinae; Assistant (Zuo): Curcuma longa and Panax notoginseng; Messenger (Shi): Alisma plantago-aquatica. In this formulation, the sovereign drug directly addresses the primary etiology (e.g., copper chelation and detoxification); the minister drugs potentiate this effect while managing core comorbidities (e.g., hepatoprotection and choleresis); and the assistant-messenger drugs moderate medicinal properties, direct therapeutic action, and mitigate potential adverse effects. Collectively, these components clear heat, drain dampness, resolve toxins, dissipate stasis, and promote purgation, thereby facilitating the elimination of excess copper. Similarly, Huangpu Tongqiao Capsule[145], a modern Chinese patent medicine, is formulated with standardized botanical extracts such as Rhei Radix et Rhizoma, Acori Tatarinowii Rhizoma, Chuanxiong Rhizoma, Ginseng Radix et Rhizoma, Polygoni Multiflori Radix Praeparata and Alpiniae Oxyphyllae Fructus. Designed to promote blood circulation, resolve stasis, tonify qi, and activate collateral vessels, it aims to improve neurological function and support recovery in conditions like post-stroke sequelae.

Huangpu Tongqiao Capsule

The advent of network pharmacology has provided modern interpretive tools and validation approaches for the effects of compound formulas. By constructing a disease-target-drug interaction network, this research method can systematically predict the key targets (e.g., ATP7B, NF-κB, and superoxide dismutase) and related signaling pathways (e.g., apoptosis, autophagy, and copper homeostasis) that multiple bioactive components in compound formulas upon which Gandouling Decoction and Huangpu Tongqiao Capsule may act. Validation of these predicted targets and pathways through in vitro and in vivo experiments has clearly revealed the multicomponent, multitarget, and multipathway synergistic mode of action of compound TCM at the molecular level[145,146]. This confirms the scientific rationality of the compatibility of compound TCM and provides a solid theoretical basis for its clinical translation, application, and subsequent new drug development[147-149]. However, its relevance to hereditary hepatic diseases remains unproven and should not be extrapolated from neurological outcomes.

CURRENT CHALLENGES AND FUTURE PERSPECTIVES

Despite the prospects exhibited by compound TCM represented by Gandouling Decoction and Huangpu Tongqiao Capsule, as well as various monomeric components such as berberine and curcumin, in the treatment of HLIDs, their translation from basic research to clinical application still faces a series of challenges and limitations.

Current challenges

Challenges in pharmacokinetics and bioavailability: Many components that exhibit efficacy in vitro and in animal models, such as curcumin and resveratrol, face issues including poor oral absorption, rapid metabolism, and low bioavailability in humans[150,151]. These limitations hinder the complete reproduction of the significant therapeutic effects observed in experiments in the human body, thereby restricting the full exertion of their clinical efficacy. Safety remains a critical consideration in the clinical application of herbal medicines. Beyond general tolerability, particular attention must be paid to herb-induced liver injury, nephrotoxicity, and the risk of contamination with heavy metals, pesticides, or adulterants. Batch-to-batch variability further complicates safety assessment, underscoring the necessity of stringent quality control and standardized extracts.

Challenges in quality control of medicinal materials and standardization of compound formulas: The therapeutic efficacy of TCM compound formulas, such as Gandouling Decoction and Huangpu Tongqiao Capsule, is highly dependent on the uniformity and stability of medicinal material quality. However, variations in factors including the origin, harvesting season, and processing technology of medicinal materials lead to fluctuations in the content of their bioactive components. Coupled with the inherent complexity of the components in compound formulas themselves, establishing unified and precise quality control standards has become extremely challenging[152,153]. Such batch-to-batch variability directly affects the reproducibility and stability of therapeutic efficacy, posing a significant barrier to large-scale clinical research and widespread clinical application.

The “black box” issue in mechanism of action research: Although network pharmacology has provided robust hypotheses for elucidating the multicomponent, multitarget, and multipathway mode of action of compound formulas, its predicted results still require extensive biological experiments for stepwise validation. Currently, our understanding remains relatively superficial regarding key questions such as how individual components in compound formulas interact precisely, how they act on final targets after being absorbed and metabolized by the body, and what constitutes the core hub of their overall regulatory network[154,155]. Thus, the black box has not yet been fully unlocked.

Lack of high-quality clinical evidence-based data: Currently, the supporting evidence mostly derives from in vitro studies, animal experiments, and small-sample or case-series clinical reports. There is a general lack of rigorously designed, multicenter, large-sample RCTs. As a result, the efficacy and safety of these TCM interventions have not been widely recognized by the international evidence-based medical community, thereby affecting their positioning within the modern medical system and the development of clinical practice guidelines.

Future perspectives and translational medicine pathways

Faced with current challenges, the future development of TCM for the treatment of HLIDs must rely on modern science and technology, adhere to the concept of translational medicine, and bridge the gap between basic research and clinical application.

Multiomics + artificial intelligence: In the future, multiomics technologies such as genomics, proteomics, and metabolomics should be integrated with artificial intelligence for big data analysis[156-158]. This is expected to systematically reveal the complete in vivo action landscape of compound formulas (e.g., Gandouling Decoction and Huangpu Tongqiao Capsule) and monomeric components (e.g., berberine and SalB), and precisely dissect the molecular networks they regulate, fully unlocking the black box of TCM actions. Ultimately, this will provide a solid theoretical foundation for precision medicine and new drug development.

Nanotechnology-based delivery systems: Nanotechnology offers a highly promising solution to the low bioavailability of components such as curcumin and resveratrol[159]. By constructing novel delivery systems (e.g., liposomes and polymeric nanoparticles), bioactive components can be protected, their targeted accumulation capacity enhanced, and their release controlled, significantly improving therapeutic efficacy and reducing dosage requirements.

Rigorously designed RCTs: The core of advancing TCM onto the international evidence-based medicine stage lies in generating high-level clinical evidence. Priority must be given to conducting rigorously designed, large-sample, multicenter RCTs to objectively and scientifically validate the clinical efficacy and safety of TCM formulas such as Gandouling Decoction and Huangpu Tongqiao Capsule. This constitutes a crucial step toward gaining widespread recognition and being incorporated into clinical practice guidelines. However, TCM should only be considered as a potential complementary approach within registered clinical trials or well controlled investigational settings, and not as a substitute for proven disease modifying treatments such as copper chelation, zinc maintenance, or phlebotomy when such therapies are indicated.

Integrated TCM-western models for precision therapy: Based on molecular mechanisms and high-level clinical evidence, future therapeutic models will no longer involve the simple combination of TCM and western medicine. Instead, they will entail integration of the strengths of TCM in systemic regulation (e.g., improving the overall internal environment) and advantages of western medicine in targeted therapy (e.g., specific copper excretion), based on precise analyses of patients’ genetic backgrounds, disease subtypes, and biomarkers[160,161]. This will enable the customization of optimal integrated TCM-western medicine regimens for individual patients.

Evidence-based medicine system construction: It is imperative to actively strengthen cooperation with international academic institutions and regulatory authorities to jointly establish an internationally recognized clinical evaluation methodology and standard system tailored to the characteristics of TCM compound formulas[162,163]. By constructing high-quality, shared clinical databases and continuously accumulating global evidence-based data, TCM can truly be promoted to play a greater role in the treatment of complex diseases such as HLIDs and gain global recognition.

CONCLUSION

HLIDs are complex, incurable, and underserved by current therapies. TCM offers a single-target, symptom-focused treatment to multicomponent, mechanism-based regulation. This review highlights the potential strength of TCM via multitarget components. The potential translational value of compound TCM formulas, guided by the Jun-Chen-Zuo-Shi principle, a roadmap to overcome challenges (multiomics, nanotechnology, RCTs) and integrate TCM into global HLID care. By merging traditional wisdom with modern science, TCM holds promise for expanding therapeutic options for HLID patients, potentially enabling a transition toward more precise and holistic management strategies.

ACKNOWLEDGEMENTS

The authors thank Dr. Gong Ling (Hangzhou Normal University) for her insightful discussions regarding therapeutic strategies for hereditary liver diseases.