Research progress in the treatment of ulcerative colitis with natural products

Abstract

Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease characterized by a protracted course and high recurrence rate. Existing clinical therapeutic agents for UC are plagued by prominent side effects and drug resistance, while natural products (NPs) have emerged as a key research direction for UC treatment owing to their advantages including wide availability, multi-target synergistic effects, and low toxic and side effects. This review summarizes the recent research advances in NPs for UC intervention, and systematically analyzes the core active components and underlying mechanisms of action of NPs these agents exert therapeutic effects primarily via anti-inflammatory, antioxidant, intestinal mucosal barrier repair, intestinal flora modulation, and immune response regulation pathways. Meanwhile, it is pointed out that NPs face challenges in clinical translation, such as complex chemical compositions, low bioavailability, and the lack of large-sample clinical validation. In the future, it is necessary to clarify their action targets and improve bioavailability by leveraging technologies like network pharmacology and formulation optimization, and conduct standardized clinical studies to facilitate the development of NPs into novel therapeutic or adjuvant agents for UC treatment.

Key Words: Ulcerative colitis; Natural products; Anti-inflammation; Gut microbiota; Clinical translation

Core Tip: This review summarizes recent research advances in natural products for ulcerative colitis, systematically analyzes their core bioactive components and potential mechanisms of action, and further identifies the challenges in clinical translation. In the future, it is imperative to clarify their therapeutic targets and conduct standardized clinical studies to facilitate the development of natural products as novel therapeutic agents or adjuvants for ulcerative colitis treatment.

INTRODUCTION

Ulcerative colitis (UC) is a lifelong inflammatory bowel disease affecting the rectum and colon. In 2023, the global prevalence of UC was estimated to reach 5 million cases, with a rising incidence worldwide[1]. Historically, UC has long been regarded as a “Western disease”, with an incidence of 300-400 per 100000 individuals in Western populations[2]. However, amid the accelerated industrialization and westernization of dietary patterns, the incidence and prevalence of UC have increased significantly in other regions including Asia, accompanied by a distinct trend toward younger age at onset. Notably, while the incidence of UC in China is lower than that in Western countries, it remains higher than in other developing nations[3,4]. The ongoing acceleration of urbanization and industrialization is expected to exacerbate the burden of UC in developing countries, posing significant challenges to global healthcare systems[5]. Currently, the pathogenesis of UC remains incompletely understood, with multiple factors including genetic susceptibility, immune-inflammatory dysregulation, and alterations in the gut microbiota implicated as contributing causes[6].

No definitive cure exists for UC to date, with the core goal of current clinical management focusing on achieving mucosal healing and sustained remission to reduce hospitalization rates and the need for intestinal resection[7]. Conventionally recommended clinical agents primarily include corticosteroids, 5-aminosalicylates, and immunosuppressants (e.g., azathioprine, methotrexate, 6-mercaptopurine)[8]. Emerging biologics and novel therapeutics including anti-tumor necrosis factor (TNF) agents (e.g., infliximab, adalimumab, golimumab), cytokine inhibitors (e.g., the anti-interleukin 12/23 agent ustekinumab), anti-integrin drugs (e.g., vedolizumab, natalizumab), and sphingosine-1-phosphate receptor modulators (e.g., ozanimod) have demonstrated efficacy in the management of moderate-to-severe UC[9-12]. Despite the expanded therapeutic landscape for UC patients afforded by these emerging biologics and agents, 10%-20% of patients still require proctocolectomy due to medically refractory disease[13].

While 5-aminosalicylates the first-line therapy for mild-to-moderate UC play a crucial role in controlling mild inflammation, long-term administration tends to disrupt gut microbiota homeostasis and induce dysbiosis. Although corticosteroids can rapidly suppress acute inflammatory flares in severe UC, 30%-40% of patients remain non-responsive to this monotherapy[14,15]. The use of immunosuppressants significantly elevates patients’ infection risk, posing a threat to their overall health. As a second-line therapeutic option for UC, emerging biotherapies have achieved therapeutic breakthroughs for some patients unresponsive to conventional treatments; however, their clinical application is limited by high costs attributed to substantial research and development (RD) investments and complex manufacturing processes, which render long-term access unaffordable for most patients and biosafety concerns[7]. For example, a phase III randomized controlled trial has demonstrated that integrin antagonists may be associated with risks such as appendicitis, infusion reactions, and increased susceptibility to infections[16]. Thus, the development of more effective therapeutic approaches for UC has become increasingly imperative. Natural products (NPs), leveraging their advantages of wide availability, multi-target synergistic effects (MTSEs), and low toxicity with minimal side effects, have emerged as a key research direction for UC treatment[17]. Therefore, this review summarizes recent research advances in NPs-based interventions for UC, systematically analyzes their core active components and underlying mechanisms of action, provides an in-depth dissection of the core bottlenecks in basic research, clinical translation, and industrialization, clarifies future development directions, and aims to offer academic references and practical guidance for advancing the innovation of NPs-enabled UC treatment.

NPS FOR UC INTERVENTION: CORE VALUE AND SCIENTIFIC BASIS

Compatibility of NPs with UC pathogenesis: Precise alignment with the multi-pathway nature of UC onset

The pathogenesis of UC involves multiple links, including inflammatory activation, mucosal damage, immune imbalance, and oxidative stress[13,18,19]. NPs can act on multiple pathological nodes simultaneously, such as alleviating intestinal inflammation[20], enhancing intestinal barrier function[21], regulating intestinal immune homeostasis[22], improving antioxidant capacity[23], remodeling gut microbiota structure[24], and restoring related metabolic disorders[25], further breaking the vicious cycle of “inflammation-damage-dysbiosis”. NPs intervene in the pathological process of UC through multiple key pathways: (1) Restoring intestinal barrier function: Reversing intestinal barrier damage in the UC state and reestablishing the structural integrity of the mucosa; (2) Regulating immune homeostasis: Correcting immune imbalance and modulating the abnormal expression of immune cells and inflammatory factors (e.g., TNF-α, interleukin-12); (3) Enhancing antioxidant capacity: Reducing UC-related reactive oxygen species levels and alleviating oxidative stress damage; (4) Remodeling gut microbiota structure: Inhibiting the proliferation of pathogenic bacteria (e.g., Escherichia coli, Klebsiella spp.) and promoting the colonization of beneficial bacteria (e.g., Firmicutes, Bacteroidetes); (5) Ameliorating metabolism-related disorders: Regulating gut microbiota-derived metabolic signals [e.g., lipopolysaccharides (LPS), bile acids, short-chain fatty acids (SCFAs)] and correcting metabolic abnormalities; and (6) Alleviating intestinal inflammation: Reversing the excessive inflammatory state of UC to the homeostatic level of a normal intestine, as illustrated in Figure 1. In addition, the active components of NPs are mostly endogenous or homologous substances in organisms, which are highly tolerated by the human body with no significant hepatotoxicity or nephrotoxicity after long-term use[26], aligning with the clinical needs of long-term maintenance therapy for UC.

Figure 1 The potential mechanisms of natural products in ameliorating ulcerative colitis through multiple pathways. This schematic diagram illustrates the pathological characteristics of ulcerative colitis (UC) (including intestinal inflammation, barrier impairment, immunological imbalance, reduction-oxidation imbalance, gut dysbiosis, and metabolic disorders) and the therapeutic effects of natural products (NPs) via six core pathways: (1) Direct anti-inflammatory effect; (2) Enhancing intestinal barrier integrity to reverse mucosal impairment; (3) Regulating immune homeostasis to restore immunological balance; (4) Improving antioxidant capacity to reduce reactive oxygen species-mediated damage; (5) Remodeling gut microbiota structure by inhibiting pathogenic bacteria (e.g., Escherichia coli, Klebsiella spp.) and enriching beneficial bacteria (e.g., Firmicutes, Bacteroidetes); and (6) Restoring metabolic homeostasis by modulating gut microbial metabolites (e.g., lipopolysaccharides, short-chain fatty acids). Collectively, NPs exert synergistic effects on multiple pathological links of UC, ultimately alleviating intestinal inflammation and restoring normal gut function. NPs: Natural products; UC: Ulcerative colitis; TNF: Tumor necrosis factor; IL: Interleukin; ROS: Reactive oxygen species; LPS: Lipopolysaccharides; SCFAs: Short-chain fatty acids.

Breakthroughs in research dimensions: Multi-level advances from basic research to clinical application

The World Health Organization reveals that 80% of the population in developing countries worldwide relies on herb-based traditional medicines for better treatment outcomes[27]. Scientific research on these active components and folk remedies, developed by diverse ethnic and cultural groups (i.e., ethnopharmacology), has made extensive contributions to the discovery and refinement of modern emerging therapeutic strategies. Numerous studies have demonstrated that core NPs components including flavonoids (containing flavonoid glycosides)[28], polyphenols (containing phenolic glycosides)[29], polysaccharides (containing glycosides)[30], alkaloids[31], and terpenoids[32] exert anti-UC effects by regulating multiple nodes, providing a solid theoretical basis for clinical application. Highly active monomers screened from medicinal plants and characteristic microorganisms (e.g., curcumin, quercetin derivatives) exhibit superior anti-inflammatory activity compared to conventional drugs. Moreover, clinical studies have confirmed that NPs may improve clinical remission rates and reduce relapse risks in UC patients[33,34].

KEY RESEARCH ADVANCES IN NP-BASED INTERVENTIONS FOR UC

Classification of core active components and their intervention efficacy

Crude plant extracts are common forms of intervention for UC in traditional medicine and daily dietary therapy, and their research can directly bridge traditional application experience with modern scientific validation, holding significant translational value. For example, Rehman et al[35] found that crude extracts of Calliandra haematocephala could ameliorate acetic acid-induced UC, confirming the therapeutic potential of crude extracts. Notably, as mixtures containing multiple active components such as flavonoids, polysaccharides, and phenolic acids, crude plant extracts often exert their therapeutic effects through the synergistic action of multiple constituents which precisely provides a direct material basis and theoretical starting point for the core advantage of NPs: MTSEs in UC. Transitioning from research on the synergistic effects of crude plant extracts to the mechanistic analysis of purified monomers thereafter can construct a complete logical framework of “traditional experience-crude extract validation-precise monomer mechanism”, more clearly demonstrating the research evolution and translational pathway of NPs in the treatment of UC.

Plant-derived NPs are currently the most well-studied, thus exhibiting prominent potential for clinical application. Quercetin, a representative flavonoid, alleviates UC by regulating the signal transducer and activator of transcription (STAT) 1/peroxisome proliferator-activated receptor γ balance and determining the alternative activation of macrophages[36]; curcumin, a representative polyphenol, can inhibit Toll like receptor (TLR) 4/nuclear factor kappa-B (NF-κB) and activate nuclear factor-erythroid 2 related factor 2 (Nrf2) to mitigate intestinal inflammation[37]; andrographolide, a terpenoid, activates the Nrf2/heme oxygenase-1 (HO-1)-mediated antioxidant response to reduce the intensity of inflammatory reactions[38]. Table 1 summarizes the specific sources, intervention mechanisms, and experimental models of core NPs components in UC over the past three years[39-87]. Notably, in research on the dextran sulfate sodium (DSS)-induced UC model, a unified DSS administration standard has not yet been established in the academic community, and significant variations exist in the DSS concentrations and intervention durations adopted by different research teams. These parameter differences not only affect the consistency of the model’s pathological phenotypes, but also render it difficult to directly compare the experimental endpoint indicators of different studies (e.g., disease activity index scores, the degree of colon length shortening, mucosal barrier integrity assay results, etc.), and may even lead to discrepancies in research conclusions.

Table 1 Summary of sources, intervention mechanisms and experimental models of core active components of natural products in ulcerative colitis[39-87].

Name	Source	Related mechanisms	Experimental models	Ref.
Nicotiflorin	San-Ye-Qing	Inhibiting the NF-κB pathway and activating the NLRP3 inflammasome to exert anti-inflammatory effects	LPS + BMDMs	Ruan et al[39]
Berberine	Coptis chinensis Franch.	Inhibiting the PI3K/AKT/mTOR pathway by targeting IRGM1	2.0% DSS induced UC in C57BL/6 J mice	Meng et al[40]
Epiberberine	Coptidis Rhizoma	Activating intestinal FXR, regulating BAs metabolism/FGF15, and relieving intestinal BAs accumulation/inflammation	3% DSS induced UC in C57BL/6 J mice	Chen et al[41]
Anemoside B4	P. chinensis	Enhancing intestinal epithelial barrier via regulating MLCK-pMLC2 signaling	3% DSS induced UC in C57BL/6 J mice	Feng et al[42]
Paeoniflorin	Paeonia emodi, Paeonia obovata	Targeting CDC42 inhibits the CDC42/JNK signaling pathway	4.0% DSS induced UC in SD rats	Hu et al[43]
Benzoylpaeo-niflorin	Baishao	Suppressing ferroptosis by regulating Nrf2/SLC7A11/GPX4 signaling pathway	3.5% DSS induced UC in C57BL/6 J mice	Tang et al[44]
Formononetin	Astragalus membranaceus	Regulating gut microbiota and M1/M2 macrophage polarization balance	2.5% DSS induced UC in C57BL/6 J mice	Xiao et al[45]
Anemoside B4	P. chinensis	Regulating Lactobacillus abundance, promoting SCFA metabolism/butyrate production, and activating the AhR pathway to inhibit ROS/NLRP3 inflammasome activation	3% DSS induced UC in C57BL/6 J mice	Wu et al[46]
Gastrodin	Gastrodia elata	Promoting gut microbiota-derived tryptophan metabolite production and inhibiting inflammation via the AhR/NLRP3 pathway	2.5% DSS induced UC in C57BL/6 J mice	Zhang et al[47]
Plantamajoside	Plantago	Regulating gut microbiota, enhancing intestinal barrier, increasing cystathionine β-synthase expression, and inhibiting the NF-κB pathway	2.5% DSS induced UC in C57BL/6 J mice	Jia et al[48]
Morin	Moraceae family	Inhibiting MAPK/NF-κB pathways, regulating gut microbiota	2.5% DSS induced UC in C57BL/6 J mice	Qiu et al[49]
Caffeic acid	Coffee, Argan	Alleviating intestinal injury by inhibiting the Toll/Imd signaling pathways and suppressing mitochondria damage-mediated apoptosis	4% DSS induced UC in drosophila	Xiu et al[50]
Curcumin, tryptophan	Turmeric	Restoring intestinal barrier function, reducing oxidative stress and inflammation, and regulating gut microbiota homeostasis	2.5% DSS induced UC in BALB/c mice	Jiang et al[51]
Vanillic acid	Vanilla bean	Inhibiting arachidonic acid metabolic pathway and promoting macrophage polarization from M1 to M2 phenotype	2.5% DSS induced UC in C57BL/6 J mice	Zhao et al[52]
Gastrodin	Gastrodia elata Blume	Enriching the Akkermansia mucinniphila population	2% DSS induced UC in BALB/c mice	Zhang et al[53]
Vanillic acid	Angelica sinensis	Regulating oxidative stress, inflammatory responses, macrophage polarization, and the AMPK signaling pathway	2.5% DSS induced UC in BALB/c mice	Ma et al[54]
Theabrownin	Fu Brick Tea	Enhancing antioxidant and anti-inflammatory capacities, regulating gut microbiota, and participating in the AhR pathway	1.5% DSS induced UC in C57BL/6 J mice	Yang et al[55]
Butylchloro-genate	Chaenomeles speciosa	Inhibiting the activation of the NLRP3 inflammasome	4% DSS induced UC in C57BL/6 J mice	Huang et al[56]
Quercetin	Vegetables and Fruits	Regulating the gut microbiota-isovanillic acid-intestinal barrier axis	3% DSS induced UC in BALB/c mice	Lei et al[57]
Proanthocyanidins	Ephedra sinica Stapf	Regulating gut microbiota and restoring impaired serum tryptophan and glycerophospholipid metabolism	4% DSS induced UC in KM mice	Lv et al[58]
TCP80-1	Tupistra chinensis Baker	Enhancing the intestinal barrier and promoting the proliferation and differentiation of intestinal stem cells into intestinal epithelial cells	4% DSS induced UC in drosophila	Wang et al[59]
Kaji-ichigoside F1	Rosa roxburghii Trat	Regulating gut microbiota and metabolism, and inhibiting the PI3K/AKT pro-inflammatory signaling pathway	3% DSS induced UC in C57BL/6 J mice	Liu et al[60]
Fraxin	Cortex Fraxini	Inhibiting ROS production, reducing pro-inflammatory cytokines, and regulating the TLR4/NF-κB and MAPK signaling pathways	2.5% DSS induced UC in C57BL/6 J mice	Sun et al[61]
Isosinensetin	Pericarpium Citri Reticulatae	Inhibiting the PI3K/AKT signaling pathway, alleviating oxidative stress and inflammatory responses, and enhancing barrier function	3% DSS induced UC in C57BL/6 J mice	Li et al[62]
Homogalacturonan	Passiflora edulis f. flavicarpa	Enhancing MUC-2 expression and promoting epithelial barrier restoration	5% DSS induced UC in Swiss mice	Mazeti et al[63]
Bergenin	Ardisia japonica	Reducing Bacteroides vulgatus abundance to regulate branched-chain amino acid metabolism, thereby inhibiting TLR4 and modulating the phosphorylation of NF-κB and mTOR	2.5% DSS induced UC in C57BL/6 J mice	Huang et al[64]
Theabrownin	Pu-erh tea	Increasing Akkermansia abundance and intestinal epithelial barrier function, regulating CD4+ T cell differentiation and Treg/Th17 balance, and inhibiting TLR2/4-mediated MyD88-dependent NF-κB, MAPK, and AKT signaling pathways	5% DSS induced UC in Swiss mice	Zhao et al[65]
Gypenosides	Gynostemma pentaphyllum	Regulating the tricarboxylic acid cycle and glutamine metabolism, modulating stem cell bioactivity, and promoting the repair of damaged mucosa	3% DSS induced UC in C57BL/6 J mice	Yang et al[66]
Glycyrrhizic acid, patchouli alcohol	Huoxiang Zhengqi	Modulating 11β-HSD1-mediated endogenous corticosterone metabolism to exert anti-inflammatory effects	2% DSS induced UC in C57BL/6 J mice	Wang et al[67]
Neohesperidin	Brassicaceae family plants	Inhibiting the MAPK/NF-κB inflammatory signaling pathway, maintaining intestinal barrier integrity, and regulating gut microbiota	2.5% DSS induced UC in C57BL/6 J mice	Ju et al[68]
Linderanine C	Lindera aggregate	Inhibiting the MAPK signaling pathway and macrophage M1 polarization	2.5% DSS induced UC in C57BL/6 J mice	Lan et al[69]
Loganic acid	Swertia cincta	Inhibiting TLR4/NF-κB-mediated inflammation and activating the SIRT1/Nrf2 antioxidant response	2.5% DSS induced UC in BALB/c mice	Prakash et al[70]
Pulchinenoside B4	Bai-Tou-weng-Tang	Targeting the CD1d-mediated AKT-STAT1-PRDX1-NF-κB signaling pathway and inhibiting NLRP3 inflammasome activation	3% DSS induced UC in C57BL/6 J mice	Li et al[71]
Rhoifolin	Citrus grandis	Activating CEMIP/SLC7A11-mediated cystine uptake and inhibiting epithelial ferroptosis	2.5% DSS induced UC in C57BL/6 J mice	Liu et al[72]
Berberine	Coptis chinensis Franch.	Modulating the bile acid/S1PR2/RhoA/ROCK pathway to restore intestinal epithelial barrier function	2.5% DSS induced UC in C57BL/6 J mice	Yu et al[73]
Gypenoside LXXV	Gynostemma pentaphyllum	Targeting the glucocorticoid receptor to inhibit NF-κB-COX2 signaling and promote M1-to-M2 macrophage polarization	2.5% DSS induced UC in C57BL/6 J mice	Wu et al[74]
Mangiferin	Pueraria tuberosa	Restoring colon length and body weight, and reducing inflammatory responses	Inducing colitis via rectal administration of 2 mL of 4% acetic acid in BALB/c mice	Dharmapuri et al[75]
Didymin	Citrus grandis	Regulating gut microbiota and altering metabolites, thereby modulating the STAT3 and NF-κB pathways	2% DSS induced UC in ICR mice	Chu et al[76]
JNUTS013	Marine fungi	Inhibiting inflammation through inducing NLRP3 protein degradation	3% DSS induced UC in C57BL/6 J mice	Wang et al[77]
Isolinderalactone	Lindera aggregata	Binding to LXRα and upregulating the expression of LXRα target genes such as ABCA1, thereby activating the LXRα pathway and inhibiting macrophage M1 polarization	2.5% DSS induced UC in C57BL/6 J mice	Huang et al[78]
Linderane	Lindera aggregata	Suppressing IL-6/STAT3-mediated Th17 differentiation and apoptosis resistance	2.5% DSS induced UC in C57BL/6 J mice	Lai et al[79]
(-)-Fenchone	Foeniculum vulgare Mill	Enhancing intestinal barrier function, exerting anti-inflammatory and antioxidant effects, and regulating immune function	Inducing colitis via rectal administration of trinitrobenzene sulfonic acid in Wistar rats	Araruna et al[80]
Ganoderic acid A	Ganoderma lucidum	Regulating gut microbiota-related tryptophan metabolism (especially 3-IAld), activating the aryl hydrocarbon receptor, and inducing IL-22 production	2.5% DSS induced UC in C57BL/6 J mice	Kou et al[81]
Oxymatrine	Sophora flavescens	Regulating ferroptosis and alleviating intestinal inflammation	4% DSS induced UC in ICR mice	Gao et al[82]
Diosmin	Citrus grandis	Inhibiting PANoptosis, regulating gut microbiota and metabolites	3% DSS induced UC in C57BL/6 J mice	Tan et al[83]
Naringenin	Citrus grandis	Activating the Nrf2 signaling pathway to exert antioxidant effects	3.5% DSS induced UC in BALB/c mice	Li et al[84]
Dihydromyricetin	Ampelopsis grossedentata	Inhibiting the formation of neutrophil extracellular traps and regulating the HIF-1α/VEGFA signaling pathway	3.5% DSS induced UC in C57BL/6 J mice	Ma et al[85]
Homoplantaginin	Salvia plebeia R. Brown	Regulating the MMP9-RLN2 signaling axis	2.5% DSS induced UC in C57BL/6 J mice	Tao et al[86]
Apigenin	Citrus grandis	Regulating mast cell degranulation via the PAMP-MRGPRX2 feedback loop	5% DSS induced UC in C57BL/6 J mice	Huang et al[87]

P. chinensis: Pistacia chinensis; NF-κB: Nuclear factor kappa-B; NLRP3: NOD-like receptor thermal protein domain associated protein 3; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; FXR: Farnesoid X receptor; BA: Bile acid; FGF: Fibroblast growth factor; MLCK: Myosin light-chain kinase; pMLC2: Phospho-myosin light chain 2; JNK: C-Jun N-terminal kinase; Nrf2: Nuclear factor-erythroid 2 related factor 2; GPX4: Glutathione peroxidase 4; SCFAs: Short-chain fatty acids; AhR: Aryl hydrocarbon receptor; IL: Interleukin; ROS: Reactive oxygen species; MAPK: Mitogen-activated protein kinase; AMPK: Adenosine 5’-monophosphate-activated protein kinase; TLR: Toll like receptor; Treg: Regulatory T cells; Th: T helper; CD: Cluster of differentiation; 11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1; SIRT1: Silent information regulator 1; STAT: Signal transducer and activator of transcription; PRDX1: Peroxiredoxin 1; COX2: Cyclooxygenase-2; LXRα: Liver X receptor α; HIF-1α: Hypoxia inducible factor 1 alpha; VEGFA: Vascular endothelial growth factor A; PAMP: Pathogen-associated molecular patterns; LPS: Lipopolysaccharides; BMDMs: Bone marrow-derived macrophages; DSS: Dextran sulfate sodium; UC: Ulcerative colitis.

Microbial-derived NPs represent an emerging research direction, as they are more conducive to gut microbiota modulation[88]. SCFAs are representative microbial-derived metabolites; for instance, butyrate, a metabolite of probiotics, alleviates ferroptosis progression in UC by regulating the Nrf2/glutathione peroxidase 4 (GPX4) signaling pathway and improving intestinal barrier function[89]. Ganoderma lucidum polysaccharides, a representative fungal polysaccharide, ameliorate colitis in rats by modulating cecal microbiota and regulating gene expression in colonic epithelial cells[90].

Although animal-derived NPs have been less extensively studied to date, their application potential remains to be explored. As a representative animal-derived NPs, propolis is a complex mixture formed by honeybees through blending resin collected from plant buds and exudates with their own secretions. The main bioactive components of propolis include flavonoids, phenolic acids, and terpenoids[91,92], which exhibit diverse biological activities such as antitumor, antiapoptotic, anti-inflammatory, antioxidant, barrier-regulating, and antibacterial effects[93]. Therefore, the therapeutic effects of propolis in alleviating UC are pleiotropic: (1) Liquiritigenin, one of its bioactive components, may alleviate colitis in rats by inhibiting the inducible nitric oxide synthase-mediated anti-inflammatory pathway[94]; (2) Chinese water-soluble propolis can downregulate reactive oxygen species levels by enhancing the activity of endogenous antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, inhibit neutrophil activity, and reduce pro-inflammatory cytokine levels simultaneously[95]; and (3) It inhibits the activation of the protein kinase C-transient receptor potential cation channel subfamily V member 1-calcitonin gene-related peptide/substance P signaling pathway, thereby reducing the release of inflammatory mediators[96]. This multi-component and MTSE fully demonstrates the unique advantages of animal-derived NPs in the treatment of UC.

Advances in mechanism research: Focus on core signaling pathways and key targets

To date, based on existing research on the pathogenesis of UC, the core mechanisms of action of NPs for alleviating UC include regulating inflammation-related signaling pathways, repairing the intestinal mucosal barrier, balancing immune function, and remodeling the gut microbiota. Numerous studies have demonstrated that NPs can exert alleviative and therapeutic effects on UC through multiple signaling pathways[97,98], such as inhibiting the nuclear transcriptional activity of NF-κB and blocking the mitogen-activated protein kinase (MAPK) signaling cascade; regulating the Janus kinase/STAT signaling pathway; targeted inhibition of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway; participating in TLRs- and NOD-like receptor thermal protein domain associated protein 3-related signaling pathways; and activating Nrf2/HO-1-related pathways. The intestinal barrier is a crucial defense mechanism in the gut that effectively protects against internal and external harmful microorganisms, and it plays an increasingly important role in understanding disease progression and developing therapeutic agents. NPs can upregulate the expression of tight junction proteins, reduce intestinal epithelial cell permeability, decrease endotoxin and antigen leakage, while promoting intestinal epithelial cell proliferation and accelerating the healing of damaged mucosa[21,99]. In addition, NPs regulate the balance of intestinal immune function, modulate the activation and differentiation of immune cells (macrophages, T cells, B cells, dendritic cells), reduce the proportion of pro-inflammatory cell subsets, and reconstruct intestinal immune homeostasis[22,100]. Dysbiosis of the gut microbiota induces and promotes the occurrence and progression of UC. After oral administration, NPs sequentially pass through the upper gastrointestinal tract (e.g., stomach, duodenum) to reach the intestinal lumen, where they are gradually metabolized and converted into SCFAs by gut-resident microbiota (including commensal beneficial bacteria such as Bifidobacteria and Lactobacilli) through enzymatic reactions like hydrolysis and fermentation. Meanwhile, NPs promote the proliferation and colonization of beneficial bacteria, inhibit the growth of pathogenic bacteria, enhance gut microbiota diversity, remodel the gut microbiota structure, and improve the gut microecological environment[24,101]. Traditional signaling pathways such as NF-κB and MAPK have long been the focus of mechanistic research on NPs-based therapies for UC. However, current studies targeting these pathways exhibit notable limitations: First, research on the NF-κB/MAPK pathways in the field of NPs-facilitated UC treatment has become increasingly saturated, as most studies merely repeatedly validate the simplistic mechanism that “NPs inhibit NF-κB activation to alleviate inflammation”, without further exploring upstream regulatory nodes or crosstalk with other signaling pathways; second, some studies overinterpret the regulatory effects of NPs on these pathways, lacking sufficient validation in in vivo models or clinical samples; third, the specificity of NP-mediated regulation of these pathways remains unclear.

In recent years, research on the pathogenesis of UC has expanded to more refined molecular levels. Emerging mechanisms, such as autophagic dysregulation[102], abnormal programmed cell death[103], ferroptosis[104], mitochondrial dysfunction[105], metabolic reprogramming[106], and abnormal post-translational modifications[107], have all been confirmed to be involved in the pathogenesis of UC. For instance, Modified Tou Nong Powder can induce autophagy and improve mitochondrial function by activating the adenosine 5’-monophosphate-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator 1-alpha signaling pathway, thereby exerting a therapeutic effect on alleviating UC in both in vitro and in vivo experiments[108]. Ferroptosis is a novel form of non-apoptotic cell death, characterized primarily by iron homeostasis imbalance and lipid peroxidation triggered by redox system disorder[109]. Studies have confirmed that inhibiting ferroptosis in intestinal epithelial cells can effectively protect the intestinal mucosal barrier and mitigate mucosal damage[110]. Therefore, targeted intervention in the ferroptosis pathway is expected to become a potential novel strategy for the treatment of UC. For example, the ameliorative effect of Scutellaria baicalensis Georgi on UC is closely associated with its regulation of lipid peroxidation and suppression of intestinal epithelial cell ferroptosis mediated by the GPX4/ACSL4 axis[111]. Gancao Xiexin Decoction may alleviate inflammatory damage in UC by regulating the TEAD4/ACSL4 signaling pathway to inhibit ferroptosis in intestinal epithelial cells[112]. However, to date, research on the anti-UC effects of NPs has mostly focused on traditional signaling pathways and gut microbiota modulation, while studies on their targeted effects against these emerging mechanisms remain scarce. Their specific regulatory targets, modes of action, and synergistic effects have not yet been fully elucidated, urgently requiring further investigation. Notably, the regulatory modes of NPs in metabolic reprogramming and their precise regulatory effects on post-translational modifications of proteins (e.g., affecting the modification levels of specific inflammatory proteins) still lack in-depth mechanistic validation and in vivo experimental support. Furthermore, the synergistic regulatory relationships between NPs and emerging mechanisms (e.g., the synergistic effects of simultaneously targeting ferroptosis and mitochondrial dysfunction) as well as the impact of structure-activity relationships on the efficiency of mechanism regulation urgently require supplementation through more basic research. These gaps provide important directions for subsequent innovative research on NPs against UC.

Clinical efficacy verification of NPs: From monotherapy to combination therapy

Basic research has clarified the therapeutic effects and underlying mechanisms of NPs from various sources in the treatment of UC, laying a solid foundation for their clinical translation. Moreover, the conduct of clinical studies on traditional Chinese medicine compound preparations and other related areas has further directly promoted the transformation of NPs from laboratory settings to clinical practice, and a clear exploration path has been formed for the verification of their clinical efficacy.

In the exploration of monotherapy, NPs have been primarily targeted at patients with mild to moderately active UC and those intolerant to conventional treatments, with several products demonstrating definitive therapeutic efficacy. For instance, Fufangkushen colon-coated capsules demonstrate non-inferior efficacy and safety compared with mesalazine enteric-coated tablets in the treatment of active UC patients presenting with the traditional Chinese medicine syndrome of damp-heat accumulation, and exert superior therapeutic effects in patients with left hemicolon involvement[113]. Achillea millefolium hydroalcoholic extract capsules can effectively improve the disease activity index and multiple inflammation-related parameters in patients with mild to moderately active UC[114]. Thymus kotschyanus extract is also capable of significantly reducing fecal calprotectin levels and simple clinical colitis activity index scores in patients with mild to moderate UC[115]. Furthermore, indigo naturalis (Qingdai) monotherapy even exhibits advantages in improving clinical response rates and facilitating mucosal healing among treatment-refractory patients, such as those with steroid dependence or a history of anti-TNF-α agent administration[116]. Polyphenon E, in turn, offers a novel therapeutic option for patients with mild to moderately active UC who are refractory to 5-aminosalicylic acid medications and/or azathioprine[117]. However, the monotherapeutic efficacy of some NPs is limited. For example, plant extracts rich in cannabidiol fail to improve patients’ remission rate and are associated with poor tolerability[118]. Although Nigella sativa powder can reduce defecation frequency, it elevates inflammatory cytokine levels without improving the disease activity index[34]. Overall, monotherapy shows limited efficacy in patients with moderate to severe UC, and is also plagued by problems such as unstable therapeutic effects and narrow population applicability.

Given the limitations of monotherapy, the combined application of NPs with conventional drugs and novel therapeutic approaches has emerged as a research hotspot in clinical practice, which enhances therapeutic efficacy and expands treatment scenarios through synergistic mechanisms. Among these strategies, the combination of NPs with conventional drugs represents the mainstream model, whose core mechanism lies in enhancing anti-inflammatory effects and regulating intestinal flora balance to achieve synergistic efficacy. For example, in a 12-week treatment of moderate active UC patients refractory to 5-aminosalicylic acid, Qing-Chang-Hua-Shi granules combined with 5-aminosalicylic acid yielded significantly higher rates of clinical remission, clinical response, and relief of mucopurulent bloody stool compared with the placebo group, with a comparable incidence of adverse reactions[119]. Systematic reviews and meta-analyses have confirmed that curcumin combined with mesalazine can markedly increase the probabilities of clinical remission, clinical response, and endoscopic response in patients, exhibiting superior efficacy to placebo with mild side effects[120]. As an adjuvant therapy to standard UC treatment, pomegranate peel aqueous extract can reduce the Lichtiger colitis activity index in patients, with a higher clinical response rate than the placebo group at week 4[121]. In addition, the combination of NPs with novel therapeutic methods has shown promising potential. For instance, fecal microbiota transplantation combined with pectin therapy can lower patients’ Mayo scores and make the composition of patients’ intestinal flora more similar to that of donors, which verifies that pectin can improve fecal microbiota transplantation efficacy by maintaining the diversity of transplanted flora[122]. Although in vitro culture experiments using colonic biopsy samples from UC patients have confirmed that oleuropein can decrease Escherichia coli-LPS-induced inflammatory factor expression and alleviate inflammatory damage to colonic tissues[123], laying a foundation for its clinical application and combination therapy exploration. Additionally, a systematic review and meta-analysis summarizing data from randomized controlled trials on herbal medicines for UC have further corroborated that indigo naturalis can significantly improve clinical response rates, while curcuma longa shows prominent advantages in clinical remission rates, endoscopic response rates, and endoscopic remission rates, with supporting evidence for its adjuvant therapeutic role[124]. These findings collectively provide robust evidence for the clinical application of NPs in both monotherapy and combination therapy for UC.

EXISTING CHALLENGES IN THE TRANSLATIONAL APPLICATION OF NPS

Disconnection between basic research and clinical translation with low translation efficiency

NPs often exhibit significant anti-inflammatory activity in vitro, exerting effects by directly inhibiting the release of inflammatory factors and regulating inflammatory signaling pathways. However, they are prone to obvious application bottlenecks after in vivo administration. Following oral administration, their active components are susceptible to degradation and destruction by gastric acid and digestive enzymes in the gastrointestinal tract. Additionally, due to characteristics such as poor water solubility and weak mucosal penetration ability, their in vivo bioavailability is generally less than 20%[125,126]. This imbalance between high in vitro activity and low in vivo bioavailability makes it difficult to effectively translate the therapeutic effects observed in animal experiments into human clinical applications, seriously hindering the clinical translation of NPs. Enterotyping (or bacterial community typing) enables the stratification of patients based on the characteristics of their gut microbiota[127]. Four enterotypes have been identified to date, namely Bacteroides 1, Bacteroides 2, Prevotella, and Ruminococcus[128]. Up to 80% of inflammatory bowel disease patients harbour the Bacteroides 2 enterotype, which is defined as a dysbiotic enterotype; while the prevalence of this enterotype in healthy individuals is less than 15%[128,129]. So significant interindividual variability exists in the therapeutic efficacy of NPs for UC, a phenomenon closely associated with patients’ individual biological characteristics: On one hand, different patients exhibit distinct gut microbiota typing. As gut microbiota serves as both metabolic carriers and therapeutic targets of NPs, differences in its composition directly influence the metabolic conversion efficiency and bioactivity exertion of NPs[130]. On the other hand, variations in patients’ genetic backgrounds (e.g., inflammation-related gene polymorphisms) also lead to differences in therapeutic sensitivity to NPs. These aforementioned factors collectively result in substantial disparities in therapeutic response rates of NPs among UC patients[13]. Currently, there is a lack of precision medication guidance systems based on individual characteristics, making it challenging to formulate personalized treatment regimens.

Prominent core technical bottlenecks and great challenges in quality control

NPs possess complex and diverse chemical composition systems. Their core active components (e.g., flavonoids, polysaccharides, terpenoids) generally have low contents in raw materials and are significantly influenced by factors such as soil, climate, season, and processing technology of the producing area’s ecological environment, leading to substantial variations in the type and content of components among raw materials from different sources[131-133]. Currently, the separation and purification technologies for active components of NPs still lack a unified standardized process. Inconsistencies in extraction solvents, separation methods, and purification purity standards adopted in different research or production links result in significant batch-to-batch variations in the final active components. This makes it difficult to ensure pharmacodynamic uniformity in subsequent pharmacodynamic evaluations and clinical applications, becoming a key bottleneck restricting the development of NPs. At the level of quality control systems, influenced by the MTSEs of NPs, the existing systems lack exclusive quality control indicators that can fully reflect pharmacodynamic effects. Moreover, current standards only focus on the detection of a single marker component, which can neither cover all pharmacodynamically relevant substances nor reflect the balance of multi-component proportions. Ultimately, this leads to insufficient control over the stability of product quality, affecting the safety and reliability of clinical applications.

Scarcity of evidence-based data and low clinical acceptance

Clinical trials of NPs for UC treatment still exhibit significant scale and design limitations. Details of relevant clinical trials over the past three years are presented in Table 2[134-142]. Most conducted studies are small sample sizes, resulting in insufficient representativeness and generalizability of the research findings, which makes it difficult for existing conclusions to fully support the widespread clinical application and promotion of NPs. Some studies have inadequate reporting on key aspects such as randomization methods, allocation concealment, and the implementation of blinding procedures, thus carrying a high risk of selection bias and performance bias. In addition, most studies have a relatively short follow-up duration (usually 4-8 weeks), which makes it difficult to evaluate the long-term efficacy and safety of NPs in the treatment of UC, and also impossible to clarify their potential impact on disease recurrence rates. Moreover, differences in therapeutic efficacy across studies may stem from multiple factors: (1) The included UC patients vary in terms of disease severity, disease duration, and comorbidity status; (2) There is inconsistency in intervention strategies, including the types of NPs used, dosage administered, treatment course, and whether combined with Western medicines, all of which are not unified among different studies; and (3) There is a lack of unified standards for outcome evaluation some studies only adopt clinical symptom scores as efficacy indicators, while others combine endoscopic scores and histological scores, leading to difficulties in directly comparing the results of different studies. Existing indicators cover multiple dimensions, such as clinical symptoms, endoscopic mucosal healing, and histological repair, but significant variations exist among different studies in the selection of core indicators, detection methods, and judgment criteria, leading to difficulties in cross-study comparison of research results. Furthermore, there are obvious gaps in safety data: Safety monitoring for long-term use (> 1 year) and safety assessments in special populations (e.g., elderly, pediatric, and pregnant patients) are relatively scarce, and the risks of potential adverse reactions remain unclear, which further restricts their clinical promotion and application.

Table 2 Summary of clinical trials of natural products for ulcerative colitis[134-142].

Natural product/active component	Trial design	Sample size	Ref.
Anthocyanin-rich extract	Multicenter, randomized, placebo-controlled, double-blind study	48	Biedermann et al[134]
Hudi enteric-coated capsule, modified Wumei pill, and Qingchang Wenzhong decoction	Multicenter, randomized, double-blind study	143	Li et al[135]
Zataria multiflora	Multicenter, randomized, placebo-controlled, triple-blind trial	92	Morvaridi et al[136]
Curcumin, resveratrol	Prospective multicenter three-arm RCT	48	Erol Doğan et al[137]
Zuoqing San	Single-center, double-blind study	126	Li et al[138]
1-kestose	Randomized, double-blind, placebo-controlled pilot trial	40	Ikegami et al[139]
Curcumin-QingDai	A retrospective multicenter adult cohort study	88	Yanai et al[140]
Icanbelimod	Single-center, double-blind study	28	Lickliter et al[141]
Pegmispotide	Double-blind study	29	Allegretti et al[142]

RCT: Randomized controlled trial.

Hindered industrialization advancement and difficulties in large-scale application

Currently, NPs still face multiple practical obstacles in the industrialization process related to UC treatment: (1) Immature production technology: The extraction and purification of NPs involve complex separation steps, resulting in a long overall production cycle and high costs. This makes large-scale production difficult, directly restricting the market launch and popularization of related products; (2) Insufficient industry-university-research collaboration mechanism: Research institutions mainly focus on laboratory-scale activity verification and mechanism elucidation, while enterprises prioritize industrial feasibility and market demand; the lack of effective connection and cooperation platforms between the two leads to an obvious disconnection between laboratory achievements and industrial production technologies; and (3) Inadequate policy support system: The approval process for natural medicines (including traditional Chinese medicine compounds and NPs derivatives) is relatively complex; currently, there is a lack of exclusive evaluation standards tailored to their multi-component and multi-target characteristics, and most still follow the approval framework for chemical drugs; this results in a lengthy approval cycle and uncertain expectations of return on RD investment, significantly affecting the RD enthusiasm of enterprises and research teams, and further delaying the industrialization process of NPs-based anti-UC products.

In summary, the application of NPs in UC treatment is hampered by multiple challenges, including inadequate depth in mechanistic research, low in vivo bioavailability, inconsistent quality control, and insufficient clinical translation evidence. These unresolved issues not only restrict the clinical transformation of NPs but also point out clear directions for subsequent research.

FUTURE DEVELOPMENT DIRECTIONS AND OPTIMIZATION PATHWAYS

Deepening mechanism research and enhancing research precision

In recent years, the in-depth integration of multi-omics technologies and network pharmacology has established a precise and efficient research system. Through the integrative analysis of multi-omics data combined with target prediction in network pharmacology, panoramic correlation analysis of the “component-target-pathway” of NPs can be achieved, rapidly identifying core active components with synergistic regulatory effects and their corresponding key therapeutic targets[143]. Single-cell omics technology, with its unique advantage in resolving cellular heterogeneity, can accurately capture the specific responses of different cell subsets in the UC intestinal microenvironment to NPs, further refining the cellular targeting and action specificity of active components[144]. Ultimately, this will clarify the core regulatory nodes of the MTSEs of NPs and elucidate the mechanisms underlying interindividual response differences.

In addition, precision modeling technology for animal models better mimics the pathophysiological characteristics of human UC, overcoming the species differences between traditional mouse models and clinical patients. It can more authentically reflect the therapeutic effects and mechanisms of NPs in vivo, such as the humanized NSG mouse model[145] and fecal microbiota transplantation mouse model[146]. A novel three-dimensional in vitro model composed of multi-layered gastrointestinal tissue that exhibits functional immune responses under inflammatory conditions, which can accelerate drug development and reduce unnecessary animal experiments by providing reliable permeability and efficacy data for emerging therapies[147]. The combined application of these technologies enables multi-dimensional mechanistic validation from the molecular and cellular levels to the whole-animal level. It not only improves the precision of target and pathway elucidation for NPs but also enhances the reliability and clinical reference value of research findings, providing robust technical support for innovative mechanism research and clinical translation of NPs.

UC is closely associated with primary sclerosing cholangitis (PSC), with approximately 5%-10% of UC patients developing PSC secondary to the disease[148]. The two disorders share common pathogenic pathways, including immune dysregulation, gut-liver axis dysfunction, dysbiosis and oxidative stress[149,150], which provides a theoretical basis for NPs to exert synergistic therapeutic effects. Recent studies have demonstrated that total astragalus saponins can ameliorate ductular reaction, inflammation and liver fibrosis in PSC mice by restoring hepatic Takeda G protein-coupled receptor 5 (TGR5) expression, inhibiting NF-κB p65 phosphorylation and secretion of inflammatory factors, and its therapeutic mechanism may be dependent on the TGR5 signaling pathway[151]. For instance, curcumin[152], Artemisia capillaris Thunb. Polysaccharide[153] and Curcumae Rhizoma[154] can alleviate the degree of liver fibrosis in PSC through signaling pathways such as NF-κB and Nrf2, which is consistent with their anti-inflammatory mechanisms in the treatment of UC. The aforementioned findings in the field of PSC research not only confirm the multi-target regulatory effects of NPs on autoimmune diseases, but also provide indirect evidence for their therapeutic potential in UC. Future research may further explore whether NPs effective in PSC treatment can be repurposed for UC therapy, especially in patients with UC complicated by PSC. Meanwhile, it is necessary to further clarify the shared molecular targets of the two diseases (e.g., gut microbiota, bile acid metabolism) to optimize therapeutic strategies.

Tackling core technologies and improving quality assurance systems

To address the core bottlenecks in the RD and application of NPs-based anti-UC therapies, joint efforts from three dimensions process optimization, quality control, and formulation innovation are required. From the perspective of separation and purification process optimization, innovative technologies such as high hydrostatic pressure, ultrasound, pulsed electric field, and supercritical fluid extraction are increasingly replacing conventional methods[155]. Furthermore, integrating real-time monitoring techniques like near-infrared online detection can enhance the extraction rate and purity of core active components. Simultaneously, traceability of raw material origins and standardized control of harvesting and pretreatment processes help reduce compositional variations among different batches of raw materials. In terms of quality control system construction, integrating multi-component quantitative analysis and fingerprinting technology enables the establishment of full-chain quality standards covering raw material access, critical control points in production, and finished product inspection. This achieves accurate quantification of core pharmacodynamic components and comprehensive characterization of product composition, ensuring product quality stability and uniformity. With regard to formulation innovation and upgrading, continuous RD of colon-targeted and long-acting sustained-release formulations is crucial to improve bioavailability and lesion targeting[156,157]. Additionally, active exploration of novel drug delivery methods such as transdermal absorption and mucosal drug delivery can overcome the limitations of traditional oral administration, expanding the application scope of NPs across different patient populations and disease scenarios[158].

Standardizing clinical research and strengthening evidence-based data

To promote the clinical translation and standardized application of NPs in UC treatment, focused efforts are required in three aspects: First, conduct multi-center, double-blind, randomized controlled trials covering over 10 tertiary hospitals with a sample size of ≥ 500 cases, strictly adhering to good clinical practice guidelines to enhance the credibility and persuasiveness of research evidence; Second, develop exclusive clinical efficacy evaluation guidelines for NPs in UC treatment, unify primary endpoint indicators such as mucosal healing rate and remission maintenance duration, as well as follow-up periods, to achieve cross-study comparability of research results; Third, systematically supplement safety data by conducting long-term (≥ 1 year) safety follow-up and clinical trials in special populations (e.g., elderly, pediatric, and pregnant patients), clarify long-term medication risks and suitability for special populations, and provide solid evidence for safe clinical medication. Finally, predictive biomarkers (e.g., gut microbiota typing, inflammation-related gene polymorphisms) need to be identified to distinguish populations sensitive to NPs monotherapy or adjunct therapy, thereby enhancing precision treatment.

Strengthening industry-university-research collaboration and accelerating industrialization translation

NPs represent a cornerstone of modern medical advancement, with their applications extending from traditional herbal therapies to the discovery of landmark drugs such as morphine and quinine. The mid-20^th century was hailed as the “golden age” for the exploration of naturally derived antibiotics, after which the research scope of NPs gradually expanded into other therapeutic fields. According to statistics, a total of 58 NP-related drugs have been approved worldwide from January 2014 to June 2025, including 45 NPs and their derived new chemical entities, as well as 13 NP-derived antibody-drug conjugates[159]. Commonly used clinical immunosuppressants such as the fungus-sourced cyclosporine and mycophenolate, and the streptomycete-derived sirolimus and tacrolimus have been approved for the prevention of organ rejection in transplant recipients[160]. Tazarotene, a bacterially derived agent, has obtained approval from the United States Food and Drug Administration for the treatment of plaque psoriasis, a chronic autoimmune skin disease[161]. For UC, the fungus-sourced drug etrasimod first received approval in the United States in October 2023 for the treatment of moderate-to-severe active UC in adults; subsequently, the European Medicines Agency issued a positive opinion in December 2023, recommending the granting of its marketing authorization[162].

To accelerate the industrialization process and clinical translation of NPs in UC treatment, a full-chain support system needs to be established: First, build industry-university-research collaborative innovation platforms to promote in-depth cooperation between universities, research institutions, and pharmaceutical enterprises, bridging the key connecting links between basic research, technological breakthroughs, and industrial production; Second, optimize industrial production processes, focus on the demands of low-cost and large-scale production, and develop high-efficiency extraction and purification technologies as well as standardized production procedures; Third, improve the policy support system national and government departments should promote the establishment of green channels for natural medicine approval, formulate exclusive evaluation standards tailored to the multi-component and MTSEs of traditional Chinese medicine compounds and NPs derivatives, and provide policy guarantees for the high-quality development of the NPs-based anti-UC industry.

Based on the above content, this paper proposes a problem-oriented matching framework that aligns the core challenges of NPs application in UC treatment with the targeted development directions, as illustrated in Figure 2. The left panel summarizes four key challenges in the current field: Low translation efficiency, technical bottlenecks and quality control difficulties, insufficient evidence-based data coupled with low clinical acceptance, and impediments to industrialization and large-scale application. Corresponding to these challenges (linked by the directional arrow), the right panel puts forward four key development directions: Deepening mechanism research and enhancing precision, tackling core technologies and improving quality assurance, standardizing clinical research and strengthening evidence-based data, and strengthening industry-university-research collaboration. This diagram clarifies the “problem-solution” logical connection in this field, providing a clear guiding framework for subsequent research, technological breakthroughs, and the industrial translation of NPs in UC treatment.

Figure 2 Core challenges and corresponding development directions for the translational application of natural products in ulcerative colitis treatment. This figure illustrates the one-to-one matching relationship between the core challenges (left light pink panel) and corresponding development directions (right light green panel) regarding the translational application of natural products (NPs) in ulcerative colitis (UC) treatment. The left panel summarizes four key challenges in the current field: Low translation efficiency, technical bottlenecks and quality control difficulties, insufficient evidence-based data coupled with low clinical acceptance, and impediments to industrialization and large-scale application. Corresponding to these challenges (linked by the directional arrow), the right panel puts forward four key development directions: Deepening mechanism research and enhancing precision, tackling core technologies and improving quality assurance, standardizing clinical research and strengthening evidence-based data, and strengthening industry-university-research collaboration. This diagram clarifies the “problem-solution” logical connection in this field, providing a clear guiding framework for subsequent research, technological breakthroughs, and the industrial translation of NPs in UC treatment.

CONCLUSION

NPs have achieved remarkable progress in UC treatment research due to their advantages of MTSEs, low toxicity, and high efficacy. They provide novel insights for clinical diagnosis and treatment, possessing both significant academic value and broad application potential. However, several challenges remain, including low translation efficiency, prominent technical bottlenecks, and insufficient evidence-based data, which require targeted breakthroughs. Through multi-disciplinary collaborative innovation such as deepening mechanism research, tackling core technologies, standardizing clinical research, and strengthening industry-university-research collaboration NPs can be transformed from laboratory achievements into clinically practical therapeutic approaches, as in Figure 2. This will facilitate the improvement of UC diagnosis and treatment quality, ultimately providing patients with safer and higher-quality treatment options.