INTRODUCTION
Acute pancreatitis (AP) is a common hospitalization-requiring gastrointestinal disease characterized by a local and systemic inflammatory response and usually manifested by severe upper abdominal pain[1]. Representing one of the most challenging conditions in gastroenterology, AP is associated with significant morbidity and mortality. Mortality for pancreatitis is approximately 1% overall[2,3]; however, among hospitalized patients with pancreatitis and organ failure or pancreatic necrosis, mortality may be as high as 30%-40%[4]. The pathogenesis of AP is complex, but inflammation and tissue necrosis are considered the main initiating pathological factors[5]. Despite decades of research into the inflammatory cascades underlying this condition, therapeutic interventions remain largely supportive, and specific targeted therapies have consistently failed to translate from promising preclinical studies to clinical success. Recent guidelines from the International Association of Pancreatology (2025) continue to emphasize the urgent need for mechanism-based therapeutic approaches[6]. The work by Jia et al[7] published in this issue offers a refreshing perspective by identifying a novel epigenetic mechanism through which rutaecarpine, a traditional Chinese medicine compound, exerts protective effects against AP.
NOVEL MECHANISTIC INSIGHTS: FBXW11 AS AN INFLAMMATORY BIOMARKER
The identification of FBXW11 as a key mediator in AP pathogenesis represents a significant advancement in understanding this complex disease. Recent breakthrough research by Tan et al[8] established FBXW11 as a novel inflammatory biomarker, directly linking its expression to immune infiltration and nuclear factor kappa-B (NF-κB) pathway activation in both pancreatitis and pancreatic cancer. Notably, FBXW11 expression exhibits a progressive pattern across the disease spectrum, from normal pancreatic tissue through AP to pancreatic ductal adenocarcinoma, thereby establishing its clinical relevance throughout disease progression. FBXW11 is an F-box protein that functions as a subunit of the SKP1-cullin-F-box ubiquitin E3 Ligase complex, serving as a fundamental regulator of cell-cycle progression and tumorigenesis[9]. While FBXW11 dysregulation has been implicated in Alzheimer’s disease[10], developmental disorders[11], and various cancers[12-14], its inflammatory role in pancreatic disease was previously unexplored. Jia et al[7] demonstrated that FBXW11 expression is significantly elevated in AP models, with overexpression exacerbating cellular damage and knockdown conferring protection against cerulein-induced injury. This observation aligns with emerging pan-cancer analyses revealing FBXW11’s prognostic and immunological significance across multiple tumor types[15]. Of particular significance, the discovery that rutaecarpine targets the histone methyltransferase enhancer of EZH2 to suppress FBXW11 expression through epigenetic modification represents a conceptual breakthrough in elucidating traditional medicine’s molecular mechanisms. The EZH2-H3 methylation-FBXW11 axis provides a unifying molecular framework linking epigenetic regulation to inflammatory control, thereby offering mechanistic insights into the sophisticated pharmacological properties of traditional therapeutic compounds.
EZH2: A CENTRAL HUB FOR INFLAMMATORY REGULATION
EZH2 is a member of the polycomb group gene family, a large class of epigenetic regulators that suppress transcription. Polycomb repressive complex 2 (PRC2), one of the two major polycomb complexes, primarily functions by altering chromatin architecture to enforce gene repression[16]. As the catalytic component of PRC2, EZH2 catalyzes the trimethylation of lysine 27 on histone 3 (H3K27me3), a modification that regulates gene expression[17]. Accumulating evidence demonstrates EZH2’s involvement across diverse pathological contexts. Li et al[18] demonstrated that EZH2 suppresses angiotensin-converting enzyme 2 expression through histone H3 methylation, with therapeutic implications for coronavirus disease. In atrial fibrosis models, EZH2 was shown to repress the transcription of CDKN2a (p16, p19) and Timp4 by establishing canonical H3K27me3 marks at their promoters[19]. Additionally, EZH2 promotes pancreatic tissue regeneration in cerulein-induced pancreatitis by silencing nuclear factor of activated T cells cytoplasmic 1[20]. EZH2’s multifaceted role in inflammatory disease regulation provides a compelling mechanistic foundation for the proposed pathway. Recent high-impact studies have elucidated EZH2’s critical regulatory function in pancreatic inflammatory conditions. Yuan et al[21] revealed that EZH2 competes with p53 to modulate inflammasome activation through long noncoding RNA (lncRNA) Neat1-mediated transcription, thereby directly regulating the inflammatory cascade. Notably, their findings showed that EZH2’s SANT2 domain maintains histone H3 lysine 27 acetylation at inflammatory gene promoters, promoting chromatin accessibility necessary for inflammatory responses. Complementing these findings, Chibaya et al[22] demonstrated that EZH2 inhibition remodels pancreatic cancer inflammation by suppressing pro-inflammatory senescence-associated secretory phenotype factors through H3K27me3-mediated epigenetic silencing. Collectively, this evidence substantiates the therapeutic potential of EZH2 as a target in pancreatic inflammatory conditions.
MECHANISTIC RIGOR AND ALIGNMENT WITH PRECISION MEDICINE IN AP
The methodological strengths of the study lie in its comprehensive and multilayered experimental design, which integrates in vitro cerulein-induced AR42J cellular models with in vivo sodium taurocholate-induced rat models to provide robust evidence for rutaecarpine’s therapeutic efficacy across diverse experimental settings[7]. This rigor is further reinforced by systematic molecular validation: Molecular docking followed by cellular thermal shift assays demonstrates a direct interaction between rutaecarpine and EZH2, while co-immunoprecipitation confirms the functional consequences of this binding. The strategic application of gain- and loss-of-function manipulations for both EZH2 and FBXW11 substantially strengthens causal inference, and the finding that FBXW11 overexpression abolishes rutaecarpine’s protective effects provides compelling evidence for pathway specificity, thereby underscoring the centrality of the EZH2-FBXW11 axis. Importantly, this mechanistic framework is highly congruent with current research directions in AP. Emerging studies have highlighted the relevance of PRC2-mediated epigenetic pathways in pancreatic inflammation. Zhao et al[23], for instance, identified the lncRNA FENDRR as a modulator of autophagy via interaction with the PRC2 complex, which includes EZH2, supporting the broader physiological significance of EZH2-dependent regulatory circuits. In parallel, increasing emphasis on biomarker-guided and mechanism-based therapies, including cytokine-driven stratification strategies, reflects a shift toward precision medicine in AP care. This trend is further reinforced by the 2024 American College of Gastroenterology guidelines[24], which highlight individualized, mechanism-targeted approaches, providing an ideal translational landscape for therapeutic strategies centered on the EZH2-FBXW11 axis.
RUTAECARPINE’S MULTI-TARGET ANTI-INFLAMMATORY PROFILE
Rutaecarpine, a major quinazolinocarboline alkaloid isolated from the traditional Chinese herbal medicine Wu-Chu-Yu (Evodia rutaecarpa), has been utilized in pharmaceutical preparations for hypertension management in China for centuries[25]. Accumulating evidence demonstrates that rutaecarpine exhibits potent anti-inflammatory and immunomodulatory effects through multiple molecular targets[26-28]. The mitogen-activated protein kinase (MAPK) and NF-κB signaling cascades constitute the primary pathways regulating inflammatory mediator transcription and biosynthesis in AP[29]. Within the MAPK family, p38 and extracellular regulated protein kinases (ERK) 1/2 play pivotal roles in cytokine expression during AP pathogenesis. Notably, p38 MAPK signaling modulates NF-κB activation, which represents a critical node in the inflammatory cascade. Activation of p38 MAPK triggers downstream protein kinase phosphorylation[30], ultimately stimulating NF-κB and amplifying the inflammatory response. By targeting these pathways, rutaecarpine significantly reduces nitric oxide production and suppresses the expression of inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-1β in lipopolysaccharide- and lipoteichoic acid-stimulated macrophages[31,32]. These anti-inflammatory properties extend beyond pancreatitis; rutaecarpine attenuates inflammation and cartilage degradation in osteoarthritis by inhibiting the phosphatidylinositol 3-kinase/protein kinase B/NF-κB and MAPK pathways, potentially through integrin αVβ3 activation[33]. Furthermore, rutaecarpine exerts antioxidative effects by activating the nuclear factor erythroid-2-related factor 2 (NRF2) pathway across diverse pathological conditions, including acute liver injury[34], colitis[35], traumatic brain injury[36], and migraine[37]. In the specific context of AP, studies demonstrated that rutaecarpine mitigates cerulein-induced inflammation in both rodent models and AR42J cells by upregulating calcitonin gene-related peptide, subsequently suppressing MAPK and NF-κB signaling[38,39].
The EZH2-FBXW11 axis identified by Jia et al[7] likely functions synergistically with these established mechanisms rather than operating in isolation. Critically, FBXW11’s documented role in NF-κB activation through inhibitor of NF-κB alpha (IκBα) ubiquitination suggests substantial crosstalk between epigenetic regulatory circuits and canonical inflammatory signaling pathways. Rutaecarpine’s suppression of FBXW11 via EZH2-mediated epigenetic silencing may therefore synergize with its direct inhibitory effects on NF-κB and MAPK pathways, culminating in enhanced anti-inflammatory efficacy. Recent mechanistic investigations have further elucidated rutaecarpine’s sophisticated anti-inflammatory profile and its potential interactions with the EZH2-FBXW11 network. Jayakumar et al[32] demonstrated that rutaecarpine inhibits NF-κB and ERK/p38 MAPK pathways by blocking IκBα and NF-κB p65 phosphorylation, thereby preventing their nuclear translocation. This mechanism directly correlates with FBXW11’s established role in NF-κB activation as identified by Tan et al[8]. Intriguingly, novel epigenetic connections have emerged from the work of Xu et al[36], who discovered that rutaecarpine promotes PGK1 ubiquitination to activate the NRF2 antioxidant pathway. This finding reveals direct engagement with protein degradation machinery analogous to FBXW11’s E3 ubiquitin ligase function, indicating that rutaecarpine may modulate FBXW11-mediated protein targeting through multiple convergent mechanisms.
While this editorial emphasizes the novel EZH2-FBXW11 epigenetic mechanism, it is essential to recognize that rutaecarpine’s overall therapeutic benefit likely derives from the integrated effects of multiple pathways operating in concert. The relative contribution of each molecular pathway may vary depending on AP etiology, disease severity, and timing of therapeutic intervention. This polypharmacological profile may actually confer therapeutic advantages for treating complex inflammatory conditions like AP, where single-target therapies have historically demonstrated limited clinical success. The multi-target nature of rutaecarpine potentially addresses the multifactorial pathogenesis of AP more comprehensively than conventional mono-targeted approaches, offering a rationale for its promising preclinical efficacy.
CLINICAL IMPLICATIONS AND THERAPEUTIC POTENTIAL
The therapeutic implications of these findings extend well beyond the immediate application of rutaecarpine in AP treatment. The identification of FBXW11 as a druggable target establishes novel therapeutic opportunities, including the development of selective FBXW11 inhibitors and modulators of its upstream regulators. Furthermore, the elucidation of EZH2-mediated epigenetic mechanisms suggests that other epigenetic modulators may similarly confer therapeutic benefit in AP, thereby broadening the therapeutic armamentarium for this condition. Recent clinical developments strongly support this therapeutic strategy. Multiple EZH2 inhibitors (tazemetostat, valemetostat) and clinical-stage compounds offer well-established pharmacological pathways for targeting this mechanism. Ongoing clinical trials investigating EZH2 inhibitors in solid tumors, including pancreatic cancer (No. NCT04705818), have established the translational infrastructure necessary for potential expansion to AP applications. More importantly, this work provides a robust scientific rationale for clinical investigation of rutaecarpine in AP patients. The demonstrated efficacy in reducing inflammatory markers, oxidative stress, and tissue damage in preclinical models, combined with the well-documented safety profile of rutaecarpine in traditional medicine, substantiates the clinical trial rationale. Recent real-world analyses demonstrate the efficacy of integrating traditional Chinese medicine with conventional medical approaches in managing mild-to-moderate AP[40].
BROADER IMPACT ON TRADITIONAL MEDICINE RESEARCH
This study exemplifies how modern molecular techniques can systematically elucidate the mechanisms underlying traditional medicine practices, potentially validating centuries-old therapeutic approaches through rigorous contemporary scientific frameworks. The demonstration that rutaecarpine can modulate epigenetic machinery highlights the inherent biological sophistication of natural compounds and reveals that traditional medicines may operate through mechanisms substantially more complex than previously recognized. Rather than crude, non-specific effects, this work demonstrates that natural alkaloids can engage sophisticated regulatory circuits comparable to rationally designed therapeutics. The epigenetic modulation mechanism identified here likely extends beyond AP to other inflammatory conditions where FBXW11 or similar epigenetic pathways play crucial roles. This interpretation is supported by recent evidence demonstrating that traditional Chinese medicine compounds modulate epigenetic regulation in inflammatory bowel disease and related gastrointestinal disorders[41,42], suggesting convergence of mechanistic principles across disease contexts. Recent bibliometric analyses of traditional Chinese medicine research in AP (2007-2023) reveal a pronounced shift toward mechanism-based investigations and molecular pathway elucidation[43], positioning this work within a broader disciplinary trend toward evidence-based traditional medicine research. This paradigmatic evolution reflects the field’s maturation from empirical observation toward systematic molecular validation, underscoring the scientific legitimacy of investigating traditional therapeutics through contemporary frameworks.
LIMITATIONS AND FUTURE DIRECTIONS
While the Jia et al’s study[7] provides compelling mechanistic insights, several important limitations merit careful consideration. The reliance on animal models, sodium taurocholate-induced rats and cerulein-stimulated AR42J cells, while necessary for proof-of-concept investigations, may not fully recapitulate the heterogeneity of human AP pathophysiology. In clinical practice, AP presents with diverse etiologies (gallstone-induced, alcohol-related, hypertriglyceridemia-associated) and severity classifications (mild, moderately severe, severe), each potentially influencing therapeutic response. The current models primarily represent bile acid-induced and hyperstimulation-induced AP; validation in human pancreatic tissue from patients with varying etiologies would be essential to establish the clinical relevance and generalizability of the EZH2-FBXW11 axis.
The pharmacokinetic properties of rutaecarpine present substantial clinical translation challenges: Low oral bioavailability, rapid first-pass metabolism yielding hydroxylated derivatives, and short plasma half-life collectively constrain systemic drug exposure. However, recent advances offer promising solutions. Structural modification strategies, including N-substituted rutaecarpine analogs, have demonstrated improved metabolic stability and enhanced anti-inflammatory efficacy[44,45]. Additionally, nano-delivery platforms, lipid-based nanoparticles or polymeric nanocarriers, could substantially enhance intestinal absorption while protecting against first-pass metabolism. Pancreas-targeted delivery systems using tissue-specific ligands represent another promising approach to maximize local drug accumulation while minimizing systemic toxicity[46].
Several additional mechanistic investigations warrant attention. The relative contribution of the EZH2-FBXW11 pathway likely varies across different AP etiologies; comparative studies across multiple disease models would clarify whether this pathway represents a universal mechanistic principle or exhibits context-specific importance. The dose-response relationship remains incompletely characterized, while the original study employed 300 μg/kg based on prior optimization, optimal dosing for different AP severities, the therapeutic window, and potential dose-dependent toxicity require systematic evaluation. Furthermore, the study’s focus on a single time point (24 hours post-induction) may not capture full temporal dynamics; time-course studies across multiple intervals (6, 12, 24, 48, 72 hours) would define the optimal intervention window and distinguish primary therapeutic effects from secondary compensatory responses.
Multi-center preclinical validation studies are essential for establishing experimental reproducibility and identifying potential confounding factors related to laboratory protocols, animal strains, or reagent variability. Human tissue validation through endoscopic ultrasound-guided fine needle aspiration or surgical specimens should accompany well-designed clinical trials stratified by AP etiology and severity. Finally, investigating whether other traditional medicine alkaloids, such as berberine, with its documented histone deacetylase modulation, operate through similar epigenetic mechanisms could reveal additional therapeutic opportunities and accelerate translation of traditional medicine wisdom into precision therapeutics[47].
RESEARCH GAPS AND NOVEL CONTRIBUTIONS
While extensive literature supports individual components of this mechanistic framework, no current investigations directly explore the rutaecarpine-EZH2-FBXW11 signaling axis in AP, rendering this work’s contribution genuinely novel and intellectually significant. The proposed mechanism is robustly grounded in converging lines of evidence. FBXW11’s well-established role as an inflammatory biomarker in pancreatitis demonstrates direct correlation with NF-κB pathway activation, while EZH2’s proven capacity to regulate inflammatory responses across diverse disease contexts, coupled with the availability of Food and Drug Administration (FDA)-approved therapeutic inhibitors, facilitates clinical translation. Rutaecarpine’s documented multi-target profile encompasses protein ubiquitination, transcriptional regulation, and NRF2 antioxidant activation, extending beyond the proposed epigenetic axis. Furthermore, established precedents exist for epigenetic modulation by structurally related alkaloids such as berberine, substantiating the plausibility of alkaloid-mediated histone methylation. Collectively, these converging elements position the proposed mechanism not as speculative hypothesis, but as mechanistically coherent and experimentally testable within the contemporary framework of epigenetic pharmacology.
CONCLUSION
The work by Jia et al[7] represents a significant advancement in AP research, providing novel mechanistic insights that bridge traditional medicine and modern epigenetics. The identification of the EZH2-FBXW11 axis as a therapeutic target offers concrete hope for developing effective treatments. Recent confirmation of FBXW11 as an inflammatory biomarker and EZH2’s established role in inflammatory regulation provide strong support for this mechanism. This study exemplifies how rigorous molecular investigation can validate traditional therapeutic approaches within modern pharmacological science. The integration of traditional wisdom with cutting-edge epigenetic research may herald a paradigm shift in drug discovery, where ancient remedies inform identification of molecular targets through sophisticated mechanistic understanding. The convergence of FDA-approved EZH2 inhibitors, validated FBXW11 biomarkers, and rutaecarpine’s demonstrated safety profile creates an optimal environment for clinical translation. Beyond AP, this mechanistic framework applies to numerous conditions where traditional medicines have shown efficacy but lacked mechanistic understanding, potentially revolutionizing integrative medicine in the era of precision therapeutics.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade A
Novelty: Grade A, Grade A
Creativity or Innovation: Grade A, Grade A
Scientific Significance: Grade A, Grade C
P-Reviewer: Zhao JN, MD, Post Doctoral Researcher, United States S-Editor: Fan M L-Editor: A P-Editor: Lei YY
