Pharmacological Potential and Molecular Targets of Tetrahydrofurofuranoid Lignans From Magnoliae Flos

Introduction

Magnoliae Flos (MF), comprising the dried flower buds of Magnolia species harvested in late winter or early spring before bloom, has been historically employed in traditional medicine for treating conditions such as allergic rhinitis, headaches, sinusitis, rheumatoid arthritis, and asthma, as shown in Figure 1. Magnolia denudata Desr.,Magnolia biondii Pamp.,Magnolia fargesii Cheng.,Magnolia sprengeri Pamp.,Magnolia liliiflora Desr.,and Magnolia kobus DC are the most frequently used medicinal materials in China, Japan, and South Korea. Currently, only a few species from the genus Magnolia are considered medicinal sources. MF is referred to as Xin-yi in China, Shin-Yi in South Korea, and Shen-i in Japan. The Pharmacopoeia of the People’s Republic of China includes M. denudata, M. biondii, and M. sprengeri.^1–3

Figure 1 Magnoliae Flos denotes fresh flower buds. After sun-drying, these buds yield the TCM material known as Xinyi, employed for various therapeutic indications. Created in BioRender. xiaohan, Y. (2025) https://BioRender.com/duizcpq.

The primary constituents of MF species are categorized into two classes: lipid-soluble and water-soluble components. Lipid-soluble compounds, typically extracted using alcoholic solvents, are abundant in volatile oils and lignans.^2,4 Lipid-soluble constituents are the primary active components of MF. Numerous recent studies have investigated the chemical composition of volatile components and lignans in this medicinal plant. TFLs, as non-volatile lignans, represent the most abundant and bioactive constituents in MF lignan studies. Due to their relatively high stability, crude extracts can be obtained through alcohol extraction (MFE) or aqueous extraction (MKE).⁵ These bioactive lignans have demonstrated efficacy in inhibiting inflammatory processes, exerting anti-allergic and anti-tumor effects, improving glucose metabolism, and providing cardiovascular protection. However, a systematic synthesis of available evidence remains lacking. This review comprehensively evaluates TFLs concerning chemical composition, clinical applications, pharmacological mechanisms, pharmacokinetic profiles, toxicological properties, and critical influencing factors. Furthermore, perspectives on future research directions are provided to facilitate the development of therapeutics derived from MF and optimize their clinical application.

TFLs represent optically active, naturally occurring dimeric compounds composed primarily of two phenylpropane (C6-C3) units interconnected by β’-β’ bonds. These structural units feature a characteristic 2,6-diaryl-3,7-dioxabicyclo [3.3.0] octane skeleton linked via positions 8–8’, 7-O-9′, and 9-O-7′, as in Figure 2a.^6,7 Structures of these compounds vary based on stereochemical configurations of oxygen-containing substituents in the hydrocarbon chain and benzene ring. As mixtures of enantiomers, they exhibit significant variation in enantiomeric composition. Optical purity of TFLs and furan lignans has not been demonstrated through chiral high-performance liquid chromatography (HPLC) analysis.^8,9 According to plasma pharmacochemistry theory, only components absorbed into the bloodstream exert pharmacological effects. Research has demonstrated that seven TFLs from MF, magnolin, fargesin, aschantin, lirirresinol B dimethyl ether, epimagnolin, eudesmin, and kobusin can be absorbed and metabolized in the bloodstream.¹⁰ As presented in Figure 2b, their chemical structures exhibit high similarity.

Figure 2 The chemical structures of bioactive tetrahydrofurofuranoid lignans isolated from Magnoliae Flos. (a) Skeletal framework of tetrahydrofurofuranoid lignans. (b) ①–⑦: Chemical structures of seven tetrahydrofurofuranoid lignans.

The earliest written record of medicinal use of Xin-yi (MF) traces back to “Shen Nong’s Classic of Materia Medica” describing only its properties, flavors, and efficacy without details about plant characteristics or geographical distribution. During the Song Dynasty, Xinyi Powder, primarily composed of Xin-yi, became a classic prescription for nasal ailments, which remains effective and in use today.¹¹ Xinyi Qingfei Decoction, originating from “The Canon of Surgery” is used to treat cough induced by lung heat and nasal congestion accompanied by thick discharge.¹² Cangerzi San, a traditional Chinese medicine prescription from “Jisheng Fang” treats rhinitis. In this formula, Cangerzi and Xin-yi are warm, pungent herbs effective in treating allergic rhinitis and asthma by opening nasal passages.¹³ Recently, MF has been widely utilized in clinical treatments, and lignans have been identified as its primary active components. Notably, tetrahydrofurofuran-type lignans are the main type absorbed into the bloodstream, exerting pharmacological effects.¹⁴ Xinfangbiyan capsules, containing Xin-yi as a primary component, are utilized to treat chronic rhinitis, sinusitis, and related conditions in traditional Chinese medicine. Several studies have isolated magnolin from this preparation.¹⁵ Xinyi Biyan Pill is therapeutically employed for managing both acute and chronic rhinitis as well as allergic rhinitis. Magnolin, detected through ultra-high performance liquid chromatography coupled with a diode array detector fingerprinting and multi-component ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, was identified as a component of Xinyi Biyan Pill.¹⁶ Another traditional Korean medicine, NDC-052, containing magnolin and epimagnolin A, originates from M. fargesii. Clinical trials have demonstrated its effectiveness in alleviating symptoms and improving pulmonary function in patients with moderate asthma, leading to extensive clinical use.^17,18

Pharmacological Properties of Tetrahydrofurofuranoid Lignans

Inflammatory Diseases

In 1987, Pan et al¹⁹ discovered that MF could antagonize platelet-activating factor. They extracted six active constituents: magnolin, fargesin, aschantin, lirirresinol B dimethyl ether, eudesmin, and kobusin, suggesting potential involvement in cardiovascular diseases, respiratory conditions, and inflammation. Numerous recent studies have demonstrated that TFLs possess significant anti-inflammatory properties, exhibiting inhibitory effects on diverse inflammatory disorders. Their actions effectively control the progression of conditions including hepatitis, osteoarthritis, pneumonia, periodontitis, neuritis, and inflammatory bowel disease. TFLs primarily exert their anti-inflammatory effects by regulating inflammatory factor production and inhibiting associated pathways.

Inhibition of TNF-α

Research has demonstrated that M. biondii extracts significantly suppress TNF-α production in LPS-induced RAW 264.7 macrophages. Eudesmin, magnolin, and lirirresinol B dimethyl ether were isolated from these extracts.²⁰ Cho et al²¹ confirmed that eudesmin markedly inhibits TNF-α production and T lymphocyte proliferation. Ahn et al²² showed that six lignans (magnolin, fargesin, aschantin, lirirresinol B dimethyl ether, eudesmin, and kobusin) effectively suppress TNF-α-induced adhesion molecule expression in THP-1 cells. Furthermore, MFE significantly decreased inflammatory mediators such as TNF-α, IL-1β, and COX-2, effectively preventing tissue damage and alveolar bone loss in periodontitis rat models.²² Collectively, lignan constituents from MF markedly inhibit the activation of numerous pro-inflammatory mediators, especially TNF-α.

NF-κB and MAPK Pathways

Numerous in vitro investigations have demonstrated that constituents including MFE,²³ MKE,²⁴ magnolin,²⁵ fargesin,²⁶ and lirirresinol B dimethyl ether²⁷ concurrently suppress NF-κB and MAPK signaling pathways in LPS-stimulated macrophages, thus reducing the production of pro-inflammatory cytokines. Epimagnolin²⁸ exhibited comparable inhibitory activity in macrophages stimulated by Phorbol 12-myristate 13-acetate (PMA). Complementary in vivo studies confirmed that fargesin alleviates ulcerative colitis²⁹ and cadmium-induced acute lung injury³⁰ by inhibiting NF-κB signaling. Additionally, fargesin simultaneously suppressed both NF-κB and MAPK pathways, markedly reducing pro-inflammatory cytokines, cartilage breakdown, and synovial inflammation in mice with collagen-induced osteoarthritis.³¹ Similarly, magnolin attenuated osteoarthritis progression by targeting NF-κB signaling and preserving cartilage integrity in osteoarthritic rat models.³² Epimagnolin and fargesin decreased ERK phosphorylation, suppressed inducible nitric oxide synthase (iNOS) expression, and lowered NO generation, thereby alleviating inflammation in human respiratory epithelial cells.³³ These observations have been substantiated through rigorous in vitro and in vivo experiments. Seven lignans, including eudesmin, magnolin, lirirresinol B dimethyl ether, epimagnolin, kobusin, aschantin, and fargesin, isolated from the CHCl₃ fraction of MF, inhibited cigarette smoke condensate-induced IL-6 expression in human airway epithelial cells through suppression of ERK phosphorylation. In murine models, these compounds significantly reduced inflammatory cell infiltration and pro-inflammatory cytokine secretion. Notably, aschantin exerted similar effects by selectively inhibiting Akt phosphorylation.³⁴ Lirirresinol B dimethyl ether demonstrated therapeutic effects in acute liver fibrosis mouse models and inhibited carbon tetrachloride-induced hepatocellular carcinoma via the NF-κB/COX-2 pathway.³⁵

TFLs also exhibit anti-neuroinflammatory effects. In vitro, aschantin, kobusin, and fargesin blocked NF-κB pathways and reduced iNOS expression in activated BV-2 microglial cells, thereby suppressing NO production.³⁶ In vivo, magnolin alleviated paclitaxelinduced cold allodynia via the MAPK/ERK pathway.³⁷

Collectively, these studies illustrate that TFLs exert anti-inflammatory properties primarily by concurrently inhibiting the NF-κB and MAPK signaling cascades. Specifically, TFLs markedly decrease phosphorylation levels of P65/P50 in the NF-κB pathway and diminish phosphorylation of ERK, JNK, and p38 within the MAPK pathway. This simultaneous blockade curtails inflammation by significantly lowering the production of critical inflammatory mediators such as TNF-α, IL-6, iNOS, COX-2, and IL-1β. Given the frequent interplay and synergistic effects observed between the NF-κB and MAPK signaling pathways, these findings provide a comprehensive elucidation of the molecular basis for TFLs’ anti-inflammatory actions, as shown in Figure 3. Moreover, MKE³⁸ was reported to suppress pro-inflammatory cytokines and ERK1/2 signaling in human keratinocytes stimulated by TNF-α and IFN-γ, while also inhibiting JAK/STAT signaling pathways, thus alleviating scratching behaviors in mice induced with 2,4-dinitrochlorobenzene to mimic atopic dermatitis. Such diverse regulatory mechanisms may be due to variations in the bioactive constituents within TFLs crude extract mixtures.

Figure 3 Under LPS-induced inflammatory conditions, the inactive NF-κB complex (p50, p65, and IκB) is activated, leading to IκB phosphorylation and degradation and subsequent activation of the NF-κB pathway. Concurrently, AP-1 is regulated by MAPK family members (p38, ERK, and JNK), promoting the release of inflammatory mediators. Tetrahydrofurofuranoid lignans have been shown to suppress activation of both pathways. Created in BioRender. xiaohan, Y. (2025) https://BioRender.com/dl0f2wz.

Others

Research has also highlighted magnolin’s protective effects on the intestinal barrier through inhibition of the PI3K/Akt pathway, thereby reducing pro-inflammatory cytokine production and alleviating colitis resembling Crohn’s disease both in vitro and in vivo.³⁹ However, another study reported that low concentrations of magnolin suppressed 5-lipoxygenase (ALOX5) expression without influencing glutathione peroxidase 4 in dextran sulfate sodium-induced colitis in mice. Interestingly, higher magnolin doses failed to produce significant effects, possibly due to concurrent inhibition of ferroptosis and intestinal epithelial cell regeneration, a hypothesis that requires additional verification.⁴⁰ Additionally, magnolin conferred protection to liver and kidney tissues by reducing oxidative stress, inflammation, and cytotoxicity induced by the chemotherapeutic agent cyclophosphamide via activation of the Nrf2/HO-1 signaling pathway.⁴¹

In conclusion, experimental evidence supports the anti-inflammatory effects of TFLs through the NF-κB and MAPK pathways, which represent the primary mechanisms regulating inflammation. Nevertheless, comprehensive investigations remain necessary for clinical validation.

Allergic Diseases

Mast cells (MCs) are pivotal mediators in allergic reactions, activated and triggered into degranulation by virtually all known allergenic stimuli.⁴² A principal activation receptor present on all mast cells is the high-affinity IgE/Fc receptor. Compound 48/80 is widely recognized as a strong inducer of MC degranulation, primarily via the MAS-related G protein-coupled receptor (MRGPRX2) on human MCs.⁴³ Calcium influx and activation of protein kinase C are critical factors in MC degranulation. Following activation, increased intracellular Ca²⁺ levels significantly promote degranulation,⁴⁴ releasing inflammatory mediators such as histamine, leukotrienes, prostaglandins, cytokines, proteases, kinases, and nitric oxide, thereby sensitizing cells.⁴⁵ As demonstrated in Figure 4, TFLs have been identified as effective inhibitors of MC degranulation by suppressing calcium signaling and reducing allergenic mediator release, providing a promising therapeutic strategy for allergic reactions.

Figure 4 Mast cell activation via two distinct pathways, IgE-dependent and MRGPRX2-mediated signaling, stimulates phospholipase C (PLCγ and PLCβ, respectively), generating IP3 and DAG. IP3 interacts with its receptor (IP3R) on the endoplasmic reticulum (ER), inducing Ca2+ release. ER calcium depletion induces STIM1 accumulation adjacent to the plasma membrane, activating ORAI1 channels and facilitating store-operated calcium entry. Increased intracellular Ca2+ subsequently activates the calcium-dependent chloride channel ANO1, resulting in chloride efflux, membrane depolarization, and amplified calcium influx, thereby establishing a positive feedback loop that enhances downstream responses. Magnolin, fargesin, aschantin, lirioresinol dimethyl ether B, epimagnolin, eudesmin, and kobusin inhibited IgE-induced histamine release from mast cells. Notably, magnolin did not suppress histamine release triggered by MRGPRX2 activation. Furthermore, magnolin, fargesin, and eudesmin effectively inhibited ORAI1 calcium channel activity, with eudesmin also exhibiting inhibitory effects on the ANO1 calcium-activated chloride channel. Created in BioRender. xiaohan, Y. (2025) https://BioRender.com/6xmgl84.

Inhibition of Histamine

As early as 1999, MKE was reported to inhibit histamine release in rat peritoneal mast cells induced by either compound 48/80 or anti-DNP IgEin a dose-dependent manner, though specific lignan constituents were not identified at that time.⁴⁶ Subsequent research isolated nine bisepoxylignans from MFE, TFLs of which showed inhibitory effects on bone marrow-derived mast cells and IgE-mediated passive cutaneous anaphylaxis in mouse models. Fargesin exhibited the most potent activity (IC₅₀ = 93.03 μM). Increased methoxylation on the benzene ring correlated with diminished anti-allergic efficacy, and symmetrical bisepoxylignans showed weaker anti-allergic effects compared to asymmetrical compounds.⁴⁷ Fargesin and eudesmin exhibited anti-allergic activities by reducing histamine and β-hexosaminidase release from MRGPRX2-stimulated MCs.⁴⁸ A systematic comparative evaluation of six Magnolia species using a compound 48/80-induced histamine release assay in rat peritoneal mast cells revealed the inhibitory potency (IC₅₀ values) in descending order as follows: M. biondii (0.37 mg/mL) being the most potent, kobus (0.68 mg/mL) > M. liliflora (7.80 mg/mL) > M. denudata (12.63 mg/mL) > M. sprengeri (24.75 mg/mL) > M. sargentiana (57.82 mg/mL). Notably, magnolin only marginally inhibited histamine release, whereas fargesin had no significant effect.⁴⁹ These contradictory findings regarding fargesin’s inhibition of the MRGPRX2 pathway may reflect substantial variations in TFLs content or composition among different Magnolia species.

Suppression of Ca²⁺ Signaling

Further studies indicated magnolin’s ability to suppress IgE/Ag-triggered pseudo-allergic responses by attenuating Ca²⁺ influx, mast cell degranulation, and chemokine/cytokine secretion, demonstrating dose-dependent effects in vitro and in vivo. Nevertheless, magnolin did not significantly affect histamine release from MCs activated by compound 48/80 or substance P,⁵⁰ indicating a lack of inhibitory effect on non-IgE-mediated activation pathways. In an in vitro study, Joo Hyun Nam’s team isolated magnolin, eudesmin, and fargesin from a 70% aqueous-30% ethanolic extract of FM (FMEtOH). Experiments demonstrated that both FMEtOH and eudesmin inhibited the classical pathway of TMEM16A Anoctamin 1 (ANO1) calcium-activated chloride channels in ANO1-overexpressing HEK293 cells and airway epithelial cells, whereas magnolin and fargesin showed negligible inhibitory effects.⁵¹ In another in vitro study, the same group found that all three compounds (magnolin, eudesmin, and fargesin) suppressed allergic responses by inhibiting Oral calcium release-activated calcium channel protein 1 (ORAI1) channel activity (a GPCR-coupled channel), CD4⁺ T-cell proliferation, and MC degranulation, with fargesin exhibiting the strongest inhibition.⁵² These results suggest ion channel selectivity differences between magnolin and fargesin, though precise mechanisms require further elucidation.

Additionally, fargesin, eudesmin, and lirirresinol B dimethyl ether suppress leukotriene synthesis through ALOX5 inhibition, thus exhibiting anti-allergic properties.⁵³ Aschantin and kobusin effectively mitigate allergic responses and significantly downregulate IL-2 production in Jurkat T cells.⁵⁴

Cancer Diseases

Cancer is a disease that can involve multiple organs and tissues. Its development involves complex cellular processes, including proliferation, survival, invasion, metastasis, and mutations.⁵⁵ Commonly activated or mutated signaling pathways in cancer include PI3K/AKT/mTOR and RAS/MEK/ERK. Additionally, the P53, STAT3, Wnt/β-catenin, and MYC pathways significantly contribute to cancer development and represent targets for therapeutic strategies.⁵⁶ Experimental evidence demonstrates that TFLs inhibit cancer cell proliferation and tumor growth (Table 1).

Table 1 Pharmacological Mechanisms of TFLs Involved in Its Anticancer Activities

PI3K/AKT/mTOR

The phosphatidylinositide 3-kinase PI3K/AKT signaling cascade is pivotal in regulating glucose metabolism, protein synthesis, cellular proliferation, and growth, and abundant evidence highlights its significance as a target in oncology.⁷¹ The serine/threonine kinase mammalian target of rapamycin (mTOR), consisting of mTORC1 and mTORC2 complexes, orchestrates AKT-driven cell growth and transformation.⁷² mTORC2 directly phosphorylates AKT at Ser473, activating it fully and subsequently regulating mTORC1 downstream activities.⁷¹ Yong-Yeon Cho and colleagues identified aschantin as targeting the catalytic site of mTOR kinase, impeding complete AKT activation, thereby inhibiting the AKT/mTORC1/P70S6K axis and selectively obstructing downstream GSK3β signaling, effectively preventing EGF-mediated transformation and proliferation of MIAPaCa-2 and LNCaP cancer cell lines.⁶² Their further investigations indicated epimagnolin notably impeded H1650 lung cancer cell proliferation via similar pathways, whereas H460 cells remained unaffected.⁶⁰ Moreover, eudesmin displayed robust antitumor efficacy against A549 lung cancer cells through inhibiting AKT phosphorylation and facilitating JNK activation, consequently inducing apoptosis both in vitro and in vivo.⁵⁹ Eudesmin also inhibited EZH2 gene expression in nasopharyngeal carcinoma (NPC) by suppressing AKT, thereby reducing NPC cell proliferation, migration, and invasion.⁶⁵

RAS/MEK/ERK

Extracellular signal-regulated kinases (ERKs), critical MAPK family constituents, function downstream of surface receptors and cytoplasmic signaling molecules. ERKs often exhibit dysregulated activity in cancers and various diseases.⁷³ Tumor promoters, including EGF and TPA, initiate phosphorylation of ERK1/2 and RSKs, facilitating G1/S transition and promoting cellular proliferation.⁷⁴ Magnolin, a primary bioactive component of TFLs, exhibits significant anticancer properties. Yong-Yeon Cho’s team demonstrated magnolin’s ability to inhibit the ERK1/2 and downstream ERKs/RSK2 pathways, mediating its anticancer effects through these critical signaling mechanisms.⁵⁷ Another study showed magnolin suppresses NF-κB transactivation by blocking ERKs/RSK2 signaling, downregulating matrix metalloproteinases (MMP)2 and 9, and effectively inhibiting lung cancer cell proliferation and migration.⁵⁸ Furthermore, systematic evaluation revealed magnolin significantly inhibited ovarian cancer cell growth, but minimally affected pancreatic, colon, and breast cancer cells. Interestingly, magnolin suppressed ERK1/2 phosphorylation in TOV-112D ovarian cancer cells, whereas it was ineffective in SKOV3 cells, possibly due to constitutive PI3K activation and p16/p53 mutations in the latter.⁶⁸ The same team confirmed that neither epimagnolin nor aschantin exerted antiproliferative or antimigratory effects via ERKs/RSK2 signaling.⁶⁰ Shengchu Zhang’s team found that magnolin effectively inhibited breast cancer progression by suppressing MEK1/2 and ERK1/2 phosphorylation, attenuating proliferation and invasion, and inducing apoptosis in triple-negative breast cancer (MDA-MB-231) cells.⁶³ These differing outcomes may stem from cell-type-specific variations in signaling regulation. A combination therapy study revealed synergistic effects between magnolin and a BRAF inhibitor (SB590885), targeting both PI3K/AKT/mTOR and ERK/MEK pathways.⁷⁰ Integration of chemotherapeutics with traditional Chinese medicine in future therapies may significantly enhance anticancer efficacy, warranting further investigation.

P53/P21

The tumor suppressor p53, functioning as a transcriptional regulator, modulates pivotal gene expressions such as CDKN1A (p21) for inducing cell cycle arrest and senescence, and pro-apoptotic genes like BCL2-associated X protein (BAX) and p53 upregulated modulator of apoptosis. Given its central regulatory role, targeting p53 has emerged as a promising cancer therapeutic strategy.⁷⁵ The CDK inhibitor p21^WAF1/CIP1 mediates p53-dependent cell cycle arrest, apoptosis, and senescence following DNA damage.⁷⁶ Recent research indicated magnolin effectively induced cell cycle arrest in prostate cancer cells, initiating apoptosis through activation of the p53/p21 signaling pathway both in vitro and in vivo, significantly hindering tumor development and cell viability.⁶⁴ Additionally, fargesin disrupted the cell cycle by suppressing CDK2/cyclin E, thereby inhibiting colon cancer cell proliferation via enhanced expression of p21^WAF1/CIP1.⁶⁷

Others

Additionally, fargesin disrupted the cell cycle by suppressing CDK2/cyclin E, thereby inhibiting colon cancer cell proliferation via enhanced expression of.⁶⁶ Interestingly, magnolin also inhibits migration and invasion in cervical cancer cells by targeting IL-10 receptor B and suppressing JNK/SP1-mediated MMP15 expression.⁶⁹ Recent studies indicate that fargesin suppresses lung cancer cell growth and proliferation by targeting pyruvate kinase muscle isozyme M2, a key rate-limiting enzyme in glycolysis, through the glycolytic metabolism pathway linked to histone Histone H3 lactylation.⁶¹

These studies highlight distinct signaling pathways through which TFLs affect various cancers. Despite their similar chemical structures, minor structural variations among TFLs significantly influence molecular targeting of cancer-related proteins.

Cardiovascular Diseases

Fargesin exhibits significant cardioprotective effects, potentially acting through β1-adrenergic receptor (β1-AR) antagonism. It safeguards cardiac tissue by suppressing the cAMP/PKA pathway and reducing ischemia/reperfusion-induced apoptosis through diminished Caspase-3 activation in experimental animal models.⁷⁷ Additionally, fargesin effectively reduces blood pressure and induces vasodilation, potentially via antioxidative mechanisms and stimulation of NO synthesis, an effect independent of dosage.⁷⁸ These findings indicate fargesin’s capability to enhance peripheral circulation and ameliorate myocardial ischemia. Moreover, fargesin significantly diminishes atherosclerotic lesions and vascular inflammation in apoE^−/− mice by enhancing reverse cholesterol transport through elevated ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 expressions mediated by the CEBPαS21/LXRα pathway, and reducing inflammation via TLR4/NF-κB pathway inhibition.⁷⁹ Consequently, fargesin holds substantial promise as a therapeutic candidate for cardiovascular pathologies.

Metabolic-Related Diseases

MKE was first reported as a potential preventive agent against type 1 diabetes. Pretreatment with MKE completely prevented low dose streptozotocin-induced diabetes in mice, accompanied by reduced NO production in RIN-m5F cells and pancreatic islets. This treatment protected β-cells from cytokine-induced toxicity through inhibition of the NF-κB pathway.⁸⁰ Recent studies show that fargesin influences metabolism and adipogenesis. Magnolin, epimagnolin, and kobusin isolated from MFE significantly enhanced basal glucose uptake in L6 myotubes, with fargesin exhibiting the strongest effect. Mechanistic studies indicated fargesin specifically acts through the insulin-mediated PI3K/Akt pathway rather than the AMPK pathway, thereby promoting GLUT4 translocation.⁸¹ However, mechanisms underlying glucose uptake stimulation by epimagnolin and kobusin remain unclear. Moreover, fargesin upregulated GLUT4 protein expression and increased phosphorylation of Akt, AMPK, and acetyl-CoA carboxylase in 3T3-L1 adipocytes and white adipose tissue of high-fat diet-induced obese mice.⁸² An in vitro study utilizing methano and dichloromethane extracts of MF(MF-MD) demonstrated that fargesin, magnolin, eudesmin, and epimagnolin inhibited key transcription factors for lipid synthesis, including Sterol Regulatory Element-Binding Protein 1, Peroxisome Proliferator-Activated Receptor γ, and CCAAT/Enhancer-Binding Protein α.⁸³ Additionally, eudesmin inhibited adipocyte differentiation by downregulating the S6K1-H2BS36p axis and suppressing Wnt gene expression in mouse mesenchymal stem cells.⁸⁴ Overall, TFLs possess therapeutic potential against insulin resistance and obesity-related diseases by promoting glucose metabolism and inhibiting adipogenesis.

Skin Anti-Darkening Effect

Early studies demonstrated MKE’s dose-dependent inhibition of B16F10 melanoma cell viability and attenuation of dermal inflammation via dual mechanisms: reducing tyrosinase and tyrosinase-related protein 1 expression and scavenging oxidative radicals.⁸⁵ Recent studies indicated MFE effectively suppressed high mobility group box 1 protein expression and migration in ultraviolet B(UVB)-exposed HaCaT cells and epidermal models, thereby diminishing inflammatory cytokine release and cutaneous damage. Bioactive constituents from MFE identified included magnolin, eudesmin, and fargesin.⁸⁶ Furthermore, in vitro and in vivo experiments demonstrated that fargesin possesses anti-melanoma properties partly mediated by suppression of the PKA/CREB and p38/MAPK pathways.⁸⁷ Conversely, another study reported MFE stimulated melanin biosynthesis in B16-F1 and HMV-II cells, isolating seven TFLs, among which magnolin promoted melanin production via activation of melanogenic enzymes (tyrosinase, tyrosinase-related protein 1, tyrosinase-related protein) through PKA and p38 MAPK-dependent signaling pathways.⁸⁸ This finding notably contrasts with earlier observations.

Osteoarticular Diseases

Magnolin suppressed IL-1α stimulation in murine models of rheumatoid arthritis, inhibiting synovial cell proliferation and reducing joint capsule inflammation.^89,90 Additionally, MFE has therapeutic potential for osteoporosis, as demonstrated by inhibition of MMPs and cathepsin K expression, thereby reducing nuclear factor-κB ligand-mediated osteoclast differentiation and bone resorption.⁹¹ Magnolin, fargesin, aschantin, and lirirresinol B dimethyl ether inhibited MMP-9 and cathepsin K activity associated with bone destruction caused by breast cancer metastasis. These lignans significantly reduced osteoclast bone resorption, possibly linked to decreased expression of the osteolytic factor parathyroid hormone-related protein mRNA.⁹²

Other Pharmacological Effects

Epimagnolin A can function as a competitive substrate for ATP-binding cassette subfamily B member 1, enhancing the sensitivity of chemotherapy drugs.⁹³ Additionally, MF-MD dose-dependently suppress intracellular reactive oxygen species (ROS) generation. Bioactive compounds isolated from these extracts include magnolin, fargesin, epimagnolin, and eudesmin, with fargesin demonstrating the greatest hydroxyl radical scavenging activity.⁹⁴ MKE also protects ovarian tissues by activating the Akt pathway and inhibiting oxidative stress.⁹⁵ Moreover, magnolin mitigates contrast agent-induced kidney injury by reducing oxidative stress, suppressing ROS production, calcium protease I, and caspase 3 activity, and increasing Bcl-2 activity.⁹⁶ Recently, TFLs derivatives have attracted significant research attention, demonstrating anti-inflammatory,⁸⁹ anti-angiogenic, anti-rheumatic,⁹⁷ and neuroprotective effects.⁹⁸ In summary, TFLs exhibit pronounced advantages in mitigating oxidative stress and scavenging free radicals.

Pharmacokinetics

Chinese herbal medicines exhibit unique advantages as effective therapeutic and preventive agents. Currently, studies demonstrate that the pharmacokinetic parameters of magnolin, fargesin, epimagnolin, eudesmin, lirirresinol B dimethyl ether, and kobusin are dose-independent after oral or intravenous administration.⁹⁹ Following oral administration, magnolin is rapidly absorbed with bioavailability (F) ranging from 54.3% to 76.4%.¹⁰⁰ Pharmacokinetic analyses indicate magnolin follows a two-compartment model in rats, characterized by rapid absorption (Tmax ≈ 1.0 h) and slow elimination (t_1/2β = 7.96 ± 2.57 h). The volume of distribution (Vd/F) was 0.012 ± 0.008.¹⁰¹ A comparative study in Sprague-Dawley rats evaluated fargesin pharmacokinetics after oral (50 mg/kg) and intravenous (20 mg/kg) administration. Oral administration showed a Tmax of 290 ± 24.49 min, Cmax of 464.38 ± 152.11 ng/mL, and an elimination half-life of 106.39 ± 84.93 min. Intravenous administration achieved peak concentrations earlier (Tmax = 20 ± 1.28 min, Cmax = 2049.0 ± 723.43 ng/mL) with a shorter half-life (80.75 ± 36.19 min). Notably, fargesin was detectable in major organs, including heart, liver, lungs, and kidneys.¹⁰² However, combined use of herbal medicines and therapeutic drugs may lead to adverse interactions. Numerous studies have focused on the human liver cytochrome P450 (CYP) enzymes (including CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, and 3A5) and uridine 5′-diphospho-glucuronosyltransferase (UGT) (including UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) to investigate TFLs metabolism in hepatocytes. Hepatic metabolism represents the principal elimination route for fargesin in both experimental animal models and human subjects. Fargesin acts as a competitive inhibitor of CYP2C9 and demonstrates time-dependent inhibitory effects on the activities of CYP2C8, CYP2C19, and CYP3A4.^103,104 Similarly, aschantin inhibits the activities of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.¹⁰⁵ Conversely, magnolin exhibits a reduced likelihood of drug interactions owing to the involvement of several CYP enzymes in its metabolic pathways.¹⁰⁶ Furthermore, eudesmin, magnolin, fargesin, epimagnolin A, and lirirresinol B dimethyl ether non-competitively inhibit UGT1A1 and competitively inhibit UGT1A3. Consequently, co-administration with drugs metabolized by these enzymes may increase the risk of drug interactions.¹⁰⁷ Therefore, pharmacokinetic drug interactions mediated by TFLs through UGT1A1 and UGT1A3 inhibition should be evaluated in vivo.

Toxicology

Current toxicological evidence regarding TFLs remains limited. In vitro, cell viability was assessed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that eudesmin exhibits concentration-dependent (2.5–80 μM) antitumor activity against A549 cells, with an IC₅₀ of 18.3 μM.⁶⁴ Using the cell Counting Kit-8 assay measured cell proliferation, magnolin reduced chondrocyte viability at concentrations ≥20 μM, with an IC₅₀ of 58.05 μM.⁴⁹ Acute toxicity and mucosal irritation tests in guinea pigs administered MF extract at 60-fold the standard dosage found no chronic toxicity or nasal mucosal irritation. Thus, these studies indicate MF is safe for nasal administration.¹⁰⁸ However, TFLs metabolism in the body remains unclear, with insufficient quantitative toxicological data available. Further experimental research is required to evaluate the safety, toxicity, and mechanisms of action for these compounds.

TFLs Content Differentiation

Our analysis revealed significant variability in TFLs content, primarily influenced by plant genetic diversity and extraction methods. Previous studies demonstrated distinct TFLs compositions in different Magnolia varieties. Wolfgang Schuhly et al¹⁰⁹ obtained dichloromethane extracts from M. liliiflora, which contained only trace amounts of magnolin. In contrast, magnolin and fargesin were undetectable in M. denudata. Subsequently, methanolic extract liquid chromatography-mass spectrometry was employed to isolate seven lignans from M. biondii. A variety of extraction methods, including solvent extraction,¹¹⁰ accelerated solvent extraction,¹¹¹ and microwave-assisted extraction,¹¹² facilitate qualitative and quantitative determination of MF components. Analytical methods include ultraviolet spectrophotometry, thin-layer chromatography, HPLC, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry.² Variations in extraction and measurement methodologies result in differing quantification of MF constituents (Table 2). This underscores the necessity of optimizing extraction techniques for efficient and practical natural product research. Due to extensive species diversity within the Magnoliaceae family, medicinal magnolia quality standardization is essential. Research indicates mitochondrial DNA heterogeneity and dynamic structural evolution arising from repetitive recombination within Magnolia species mitochondria.¹¹³ Controlling genetic diversity among MF varieties could effectively address this challenge. While TFLs are primary bioactive components in MF and also present in magnolia officinalis leaves and bark,^114–116 these sources were not addressed in the present study.

Table 2 Chemical Compounds of Magnoliae Flos: a Comparison of Different Extraction and Analytical Techniques

Discussion and Perspective

The review covers biomolecules, pharmacology, pharmacokinetics, and toxicology, providing valuable insights into TFLs; however, several issues require further investigation. First,the effects of fargesin isolated from different crude extracts on the inhibition of the MRGPRX2 pathway are inconsistent. Multi-omics approaches (metabolomics-transcriptomics) are recommended to investigate mechanisms underlying the actions of crude extracts and isolated compounds. Second, fargesin demonstrates cardiovascular protective effects and may function as a potential β1-AR antagonist. Furthermore, fargesin demonstrates considerable potential in modulating glucose and lipid metabolism, positioning it as a promising candidate for hypoglycemic therapeutic development. However, further robust experimental and clinical data are required to substantiate this potential and elucidate the underlying mechanisms.Third, the effects of TFLs on melanogenesis are contradictory. Although their potential antioxidant and free radical-scavenging activities have been confirmed, further comparative studies among the seven identified TFLs are needed. Fourth, TFLs exhibit broad anti-tumor activity, and studies suggest magnolin may enhance chemotherapeutic drug sensitivity, indicating potential synergistic effects between TFLs and chemotherapy agents. Fifth, toxicological evidence remains insufficient, relying predominantly on in vitro studies. Comprehensive in vivo toxicological and safety evaluations are thus necessary. Sixth, lignan content and quality in MF vary significantly based on cultivar, geographical origin, and processing methods. To ensure experimental reproducibility, fingerprint profiles should be updated regularly, and a one-test-multiple-evaluation approach should be employed to confirm cultivar identity and origin. Seventh, some studies utilized MKE. As lignans are lipophilic compounds with limited water solubility, the use of water extracts may result in the loss of TFLs components and inclusion of water-soluble active constituents, such as alkaloids and flavonoid glycosides, potentially causing experimental bias. Therefore, future studies should focus on evaluating the bioactivity of isolated components from crude extracts through in vitro and in vivo experiments. Eighth, this review has limitations, as it summarizes only the seven TFLs known to be absorbed into the bloodstream, rather than covering all TFLs.

Conclusion

TFLs, as primary bioactive lignans from MF, exhibit potent pharmacological activities, including anti-inflammatory, anti-allergic, anticancer, cardiovascular protective effects, regulation of glucose and lipid metabolism, inhibition of melanogenesis, and treatment of osteoarticular diseases. These effects primarily involve modulation of the NF-κB, MAPK, PI3K–AKT, P53/P21, cAMP/PKA, Nrf2/HO-1, and LIF/Stat3 pathways. Based on existing evidence, MF represents a promising traditional Chinese medicinal herb with multiple pharmacological properties; however, it remains underappreciated clinically, with use predominantly limited to rhinitis, headache, and asthma. This review provides scientific evidence supporting the further development and broader application of TFLs from MF.