Emerging evidence has linked high dietary fructose intake with adverse health outcomes, yet its role in colitis-associated colorectal cancer (CAC) remains underexplored. Here, we demonstrate that high fructose consumption aggravates intestinal inflammation and significantly promotes tumorigenesis in an AOM/DSS-induced CAC model via activation of the EREG-EGFR signaling axis. We first developed the Food∩TCM database, which encompasses 112 medicine and food homologous TCM, along with their chemical compositions. Using the network-based pharmacological intelligence platform, we identified Laminaria japonica (kelp) and its bioactive components-fucoidan and dieckol-as promising dietary interventions. Dieckol was found to target the RNA/DNA-binding protein CNBP, which has traditionally been regarded as a positive regulator of pro-inflammatory gene expression, but here was shown to enhance its nuclear localization under inflammatory conditions and thereby repress Ereg transcription. Notably, fructose promoted O-GlcNAcylation-mediated stabilization and secretion of EREG in inflammatory fibroblasts, contributing to tumor progression. Together, these findings reveal the tumor-promoting effects of dietary fructose in CAC and highlight CNBP as a key regulator restraining Ereg expression. Our findings underscore the significance of integrating food-based strategies into chronic disease prevention, and support the development of Laminaria japonica-derived compounds as safe, long-term dietary agents for managing colitis-associated colorectal cancer.

BackgroundPsoriasis is a common chronic inflammatory skin disease with a high incidence, imposing a substantial global disease burden. As a low-cost complementary and alternative therapy, traditional Chinese herbal formulations have been widely used in clinical practice in China for the treatment of psoriasis. However, systematic analyses of their application value based on traditional Chinese medicine (TCM) syndrome patterns or treatment outcomes remain relatively limited.ObjectiveWe aim to systematically assess the efficacy and safety of common traditional Chinese herbs in the treatment of patients with psoriasis.MethodsWe conducted a systematic literature search in PubMed, Web of Science, SciFinder, WanFang Database, and China National Knowledge Infrastructure (CNKI). The literature meeting the predefined inclusion criteria was subjected to a secondary screening process. Meta-analysis was subsequently conducted using Review Manager software (version 5.4.1).ResultsA total of 47 papers involving 3,675 patients were included in the study. All TCM (herbal formula) groups showed positive effects in enhancing the treatment efficiency of different types of psoriasis. In particular, herbal medicines had a more considerable role in managing arthropathic psoriasis compared to other types of psoriasis. In terms of reducing Psoriasis Area and Severity Index (PASI) scores, TCM formula treatment showed marked benefits in pustular psoriasis. As for the improvement in TCM symptom indicators, patients with erythrodermic psoriasis (EP) showed better efficacy. For psoriasis accompanied by blood dryness, herbal medicines were more effective in reducing Dermatology Life Quality Index (DLQI) scores.ConclusionThe results indicate that TCM formulations included in this review are beneficial for reducing PASI scores, DLQI scores, and TCM symptom scores among patients with different types of psoriasis. The most commonly used herbal formula was Blood cooling and detoxification formula, followed by Taohong Siwu decoction and Blood nourishing and detoxifying formula. Nevertheless, more rigorously designed studies on herbal medicines are warranted to enhance the overall quality of research in this field going forward.

Metabolic reprogramming and epigenetic remodeling are critical features of tumorigenesis. The process of metabolic reprogramming causes metabolites like Succinyl-CoA to accumulate. Succinylation, which depends on succinyl-CoA as the direct donor group, plays a crucial role in regulating cancer metabolism. This involves the transfer of the succinyl group to the lysine residues of substrate proteins resulting in the alteration of the conformation and function of the proteins, modulating several signaling pathways, many of them involved in metabolism. There is growing evidence that succinylation can alter the activity and stability of metabolic enzymes and reshape metabolic networks. Furthermore, it precisely regulates gene expression through the epigenetic modification mechanisms of the histones and non-histone proteins. Lysine succinylation is thus a crucial hub linking tumor metabolic reprogramming and epigenetic remodeling. This review systematically summarizes the dynamic regulatory mechanisms of lysine succinylation and its critical roles in tumor metabolic reprogramming and epigenetic regulation. In the end, we discuss the crosstalk between succinylation and other post-translational modifications (PTMs) as well as recent advances in cancer therapies targeting succinylation.

Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal components in tumor microenvironment (TME), which participate in key processes such as extracellular matrix remodeling, immune regulation, metabolic support and treatment tolerance. In recent years, with the development of single-cell sequencing and spatial omics technology, people's understanding of CAFs has gradually changed from unified cancer cell population to a dynamic cell collection with diverse sources, continuous states and heterogeneous functions. Numerous studies have shown that CAFs have a high degree of dynamic plasticity, and their phenotype can undergo reversible or semi-reversible transformation driven by different microenvironmental signals. The plasticity of CAFs not only explains the functional heterogeneity of CAFs across studies, but also provides a theoretical basis for changing the therapeutic strategy of targeting CAFs from removal to reprogramming. Among them, it is a significant advantage of traditional Chinese medicine (TCM) to reprogram CAFs through network regulation. This article systematically reviews the source and classification system of CAFs. In addition, aiming at the off-target and drug resistance problems in tumor treatment, this article focuses on the unique mechanism of traditional Chinese medicine monomers and compounds reprogramming CAF phenotype with the synergistic advantages of multi-component, multi-target and multi-pathway. This paper aims to provide a new theoretical basis and strategic direction for breaking through the bottleneck of tumor treatment.

The spatiotemporal dynamics of protein kinase diffusion govern signal activation cascades, thereby modulating fundamental cellular functions. Pseudokinases, catalytically inactive members of the protein kinase superfamily, utilize noncatalytic signaling mechanisms to exert pivotal cellular functions and are frequently dysregulated in human diseases. While nanoscale dynamics of catalytically active receptors regulate signaling integrity, the functional significance of pseudokinase spatial organization remains unknown. Here, using aptamer-based single-molecule tracking in living cells, we observed heterogeneous diffusion modes of pseudokinase PTK7 (confined, Brownian, and directed motion). Specifically, spatially PTK7 diffusion coefficients (D) quantitatively correlate with metastatic potential across pancreatic, colorectal and breast cancer cell lines. Functional validation demonstrates that antibody-mediated PTK7 immobilization suppresses invasion, while Epithelial-Mesenchymal Transition (EMT) induction accelerates diffusion kinetics to promote metastasis. Crucially, faster PTK7 mobility increases stochastic collision frequency with tyrosine kinase-like orphan receptor 2 (ROR2), enhancing complex formation to robustly activate the WNT/PCP pathway. Moreover, in patient-derived primary cells, accelerated PTK7 kinetics positively correlate with invasive and metastatic phenotypes, confirming the clinical relevance of this biophysical regulatory mechanism. This work establishes pseudokinase spatial dynamics as a biophysical regulator of tumor progression, revealing a non-catalytic paradigm where receptor diffusion kinetics encode cellular behavior through stochastic signaling potentiation.

Pancreatic cancer is known as the "king of cancers", mainly due to its aggressive metastatic potential and significant heterogeneity. The liver represents the most frequent site of distant metastasis in pancreatic ductal adenocarcinoma (PDAC). Currently, effective treatment options remain critically limited for patients diagnosed with PDAC-derived hepatic metastases. In our research, we integrated single-cell transcriptomic data from multiple samples to delve into the heterogeneity of epithelial cells. We identified a subtype of malignant metastatic epithelial cells and identified CYBA, which encodes the p22phox protein, as a key molecular target promoting hepatic metastasis in PDAC. Through experimental validation, we confirmed that p22phox was highly expressed in pancreatic cancer samples with hepatic metastasis, and its knockdown inhibited the migration of pancreatic cancer cells and metastasis to the liver. Mechanistically, p22phox activated the PI3K-AKT signaling pathway and increased MLC2 phosphorylation, facilitating the polymerization of motor proteins in pancreatic cancer cells and promoting tumor metastasis. NOX inhibitors were found to suppress PI3K-AKT and p-MLC2 pathways, as well as inhibit the migration of pancreatic cancer cells and metastasis to the liver. Therefore, targeting the activity of p22phox in pancreatic cancer may emerge as an effective therapeutic strategy for treating hepatic metastasis in PDAC patients.

This study prepared novel wax-based composite gelators using natural waxes and anthocyanin-soy lecithin complexes (ASC). These were used as gelators to construct oleogels, aiming to improve their digestion characteristics and storage stability. The results indicated that when anthocyanins were embedded in the wax system in form of phospholipid complexes, they exhibited good dispersibility. Combined FTIR and SEM analyses showed that ASC was uniformly dispersed in waxes primarily through van der Waals forces. The critical gelation concentration of these composite gelators was largely unaffected. The resulting oleogels maintained β' type crystal structure, but showed significantly decreased lightness, hardness, and gelation temperature (Tsol-gel). Microstructural analysis revealed that the crystals in the composite gelator oleogels were more dispersed, allowing for uniform oleogels system. In vitro digestion experiments showed that different gelators had varying effects on lipolysis, with ASC-CLWO exhibiting the lowest free fatty acid (FFA) release rate. After 8 days of accelerated storage in an oven at 60 °C, ASC-CLWO maintained lower peroxide value (PV) and malondialdehyde (MDA) levels, reaching only 9.2 mmol/kg and 1.2 mg/kg, respectively, demonstrating superior storage stability. Overall, this study offers insights for developing novel hydrophilic antioxidant-fortified composite gelators and their utilization in specialty oil development within the food industry.

SHP2 is a key oncoprotein and a promising target in various types of blood cancers and solid tumors. Here, we report the discovery of a novel series of dimeric pyrazolo[3,4-d]pyrimidin-4-one derivatives as potent SHP2 inhibitors. Among them, compound A4 exhibited potent inhibitory activity against both SHP2WT and SHP2E76K, and it demonstrated dose-dependent activity against the SHP2 protein tyrosine phosphatase (PTP) domain. At the cellular level, A4 significantly suppressed the proliferation of MV-4-11, KYSE520, HCT116, MDA-MB-231 and HepG2 cell lines. Further mechanistic studies revealed that A4 downregulated SHP2-mediated phosphorylation of AKT and ERK, and induced apoptosis in MV-4-11 cells. Molecular docking revealed a comprehensive network of interactions between A4 and the SHP2-PTP domain, providing a structural basis for its potent inhibitory activity. Collectively, this work identifies compound A4 as a promising selective SHP2 orthosteric inhibitor with a distinct chemical scaffold.

BACKGROUND:Pulmonary fibrosis (PF) represents a spectrum of chronic lung disorders for which effective therapeutic options remain limited. Shegan Mahuang Decoction (SGMH) is a traditional Chinese medicine with potential therapeutic effects for respiratory system diseases. The precise mechanism of SGMH in treating PF has not yet been elucidated. PURPOSE:This study aims to investigate the effectiveness and mechanism of SGMH in the treatment of PF. METHODS:To investigate the effect of SGMH on PF, we established a mouse model and assessed inflammatory and neutrophil extracellular traps (NETs)-related markers. The target gene of SGMH was screened through integrated multi-omics analysis. The mechanisms of SGMH were explored through a series of experiments, encompassing NETs depletion with DNase I, the Pad4-/- mouse model, and pharmacological modulation via intraperitoneal administration of recombinant CCL3 (rCCL3) or a CCL3 neutralizing antibody (anti-CCL3). RESULTS:SGMH ameliorated Bleomycin-induced lung tissue damage. It also inhibited pulmonary inflammation and NETs formation. Both DNase I-mediated NETs clearance and the Pad4-/- mice model showed that SGMH could not further ameliorate PF, indicating that SGMH blocks the PF development by inhibiting NETs formation. Multi-omics analysis and experimental validation found that SGMH inhibits NETs formation by targeting CCL3. Administration of rCCL3 restored NETs formation and attenuated the anti-fibrotic effect of SGMH. Moreover, treatment with anti-CCL3 alone inhibited PF, whereas its combination with SGMH did not further enhance the therapeutic effect. CONCLUSION:This study demonstrated that SGMH ameliorates PF progression by inhibiting CCL3-mediated NETosis, suggesting its potential clinical application for PF treatment.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is closely linked to gut microbial imbalance marked by loss of beneficial microbes and overgrowth of pathogens. Christensenella intestinihominis, a bacterium that associated with intestinal homeostasis, is depleted in patients with ulcerative colitis (UC), yet its therapeutic potential against this disease remains to be elucidated. Here we demonstrate that C. intestinihominis AF73-05CM02, a strain isolated from Chinese individual, alleviates colitis. In healthy human gut, C. intestinihominis co-occurs with beneficial microbes in strongly connected networks, while these interactions are disrupted in UC. We employ the dextran sulfate sodium (DSS)-induced murine colitis model, a widely recognized preclinical model for investigating intestinal inflammation. In this model, oral gavage with AF73-05CM02 mitigates weight loss, ameliorates colonic injury, improves intestinal health markers, and reverses colon damage. It exerts these effects by reducing harmful bacteria such as Helicobacter species and increasing beneficial taxa like Akkermansia, while enhancing the intestinal epithelial barrier integrity and regulating immune responses. These findings indicate AF73-05CM02 may aid in the treatment of inflammatory bowel disease by restoring a healthy gut microbial community.

While classically viewed as a mechanical scaffold, the skeleton is increasingly recognized as a dynamic endocrine and sensory hub that integrates systemic biophysical and biochemical cues. In this Review, we rethink skeletal physiology by proposing the “Skeletal Connectome”, a network medicine framework that links circuit-level remodeling programs to multi-organ homeostasis. Structurally, we first distill the cellular logic of bone remodeling, emphasizing how osteoblasts, osteoclasts, and osteocytes act as plastic network nodes whose state transitions are constrained by topology, compartmentalization, and metabolic/biophysical gating. We subsequently map macroscopic connectome architecture, detailing bidirectional axes coupling bone to the immune, metabolic, neural, and muscular systems. Within this framework, we systematically re-evaluate diverse skeletal disorders, spanning mechano-metabolic degeneration, autoimmune disease, endocrine–metabolic fragility, and bone metastasis. We conceptualize these conditions as resulting from specific disruptions in systemic communication networks. From a translational perspective, this connectome paradigm guides the evaluation of precision therapeutics, such as targeted protein degradation and mRNA-based drugs, designed to rewire dysfunctional circuits. Finally, we discuss emerging concepts like digital skeletal twins and in silico clinical trials, highlighting their promising conceptual-translational status—rather than established clinical tools—to eventually complement real-world evidence in future personalized regimen design.

Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2+) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen, frequently contact Nefh+ nerve fibers. Moreover, Nefh deletion in Vglut2+ glutamatergic neurons drives skin fibroblast senescence and collagen loss, whereas additional glutamate improves skin aging phenotypes. Mechanistically, cyclin-dependent kinase 5 (Cdk5) interacts with both Nefh and Vglut2 and maintains glutamate release and collagen homeostasis. Additionally, in skin fibroblasts, solute carrier family 1 member 3 (Slc1a3) governs the collagen-promoting and anti-senescence functions of glutamate. Together, these findings reveal Nefh-mediated glutamatergic neuromodulation of skin aging and provide therapeutic targets for aging-related skin disorders.

Colorectal cancer poses a significant clinical challenge, with an alarming annual incidence of nearly 1.88 million new cases and limited therapeutic strategies, especially for advanced stages. The tumor microenvironment represents a complex ecosystem encompassing tumor cells, immune cells, cancer-associated fibroblasts, and extracellular matrix. This ecosystem is pivotal in orchestrating the trajectory of colorectal cancer evolution and can be divided into six microenvironments: acidic, hypoxic, metabolic, immune, microbiota, and stromal. The tumor microenvironment has increasingly garnered attention in oncological research, as modulating these environments presents novel therapeutic avenues for colorectal cancer. This review provides a comprehensive evaluation of the capacity of natural products to modulate the tumor microenvironment and augment colorectal cancer therapeutic outcomes. Additionally, this review underscores seminal clinical and preclinical studies, providing valuable insights to unlock the full potential of natural products in the development of novel drugs to effectively address the challenges posed by colorectal cancer.

Keloids represent a paradigm of fibroproliferative disorders marked by abnormal extracellular matrix deposition, yet the neuronal-stromal interactions driving fibroblast dysregulation remain poorly understood. Through single-cell RNA sequencing of human keloid specimens, we identify RUNX family transcription factor 2 (RUNX2)+ osteogenic fibroblasts exhibiting ectopic integrin-binding sialoprotein (IBSP) deposition, consistent with a hybrid fibro-osseous reprogramming. Keloid fibroblasts display catecholamine response signatures, correlating with excessive tyrosine hydroxylase-positive adrenergic innervation in keloid stroma. Crucially, β1-adrenergic receptor (ADRB1) activation by epinephrine/norepinephrine induces IBSP production exclusively in keloid-derived fibroblasts via canonical cAMP-PKA-CREB signaling. Through detailed mechanistic analysis, we demonstrate that CREB-activated Translin (TSN) facilitates nuclear-to-cytoplasmic IBSP mRNA transport, enabling efficient translation in RUNX2+ fibroblasts. Therapeutic interventions targeting catecholamine biosynthesis or adrenergic innervation, and pharmacological inhibition or genetic ablation of ADRB1 effectively prevent keloid-like pathology in a rodent model. Our study provides the demonstration of neuronal-adrenergic signaling driving fibrotic/osteogenic matrix overproduction through TSN-mediated RNA trafficking, revealing therapeutic targets for keloid management.

Artemisinin and its derivatives (ARTs) have attracted increasing interest in oncology as candidates for drug repurposing, supported primarily by broad antitumor activity in preclinical models and only limited early clinical evidence. In this review, we organize the available literature into ten recurrent and partly overlapping mechanistic dimensions, including redox disruption, direct target engagement, epigenetic, post-transcriptional and post-translational regulation, metabolic reprogramming, induction of multiple tumor-cell death programs, proliferation restraint, inhibition of angiogenesis, suppression of invasion and metastasis, remodeling of the tumor immune microenvironment, and therapeutic sensitization. Current evidence further suggests that dysregulated heme metabolism and iron handling in malignant cells may provide a recurrent upstream biochemical context for endoperoxide activation, oxidative stress, and target perturbation. These upstream events are linked to diverse downstream effects on tumor survival, proliferative capacity, metastatic behavior, immune regulation, and treatment response, supporting a view of ARTs as pleiotropic and context-dependent modulators of tumor biology rather than agents acting through a single dominant downstream mechanism. This mechanistic breadth may help explain their reported activity across diverse malignancies and their ability to enhance sensitivity to chemotherapy, radiotherapy, targeted therapy, and immunotherapy in preclinical settings. However, clinical translation remains constrained by incomplete mechanistic resolution, context-dependent heterogeneity, the lack of robust predictive biomarkers, and pharmacokinetic as well as delivery limitations. Overall, this review provides a structured overview of the anticancer pharmacology of ARTs and highlights future priorities in biomarker development, patient stratification, and rational combination strategies.

Background Colorectal cancer often develops from adenomas over years, necessitating early intervention. Myeloid-derived suppressor cells (MDSCs) are major immune suppressive cell types in colon cancer development from adenomas through early inflammation-induced emergency myelopoiesis. Cannabidiol (CBD) is reported to function in psychosis, coronavirus infection and some cancers through immune regulation. However, its target and underlying mechanisms in colorectal adenomas are unknown.Methods The antitumor effect of CBD was validated in two classical colorectal adenomas models including azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced mice model and high-fat fed Apcmin/+ mice model. Single-cell RNA sequencing was used to identified the immune environment change after CBD treatment in mice colorectal adenomas. Target responsive accessibility profiling was used to find the target of CBD in MDSCs. Subsequently, multiple immunology assays and molecular biology experiment were employed to explore the adenomas prevention mechanisms of CBD.Results Here, we found that CBD prevented the incidence of colorectal adenomas in AOM/DSS model and high-fat diet fed Apcmin/+ mice model. Our single-cell RNA sequencing data and the results of immunofluorescence revealed that CBD treatment significantly decreased the number of MDSCs in both two colon adenomas models. Mechanistically, CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, inhibiting its function in translational elongation and subsequent C/EBPβ synthesis. This disruption suppressed the differentiation and generation of MDSCs, leading to enhanced T-cell activation and prevention of colorectal adenoma progression.Conclusion Our findings reveal EEF1B2-mediated C/EBPβ protein synthesis as a crucial pathway in MDSC generation and highlight the potential of CBD as an early intervention strategy for colorectal adenomas.

Traditional Chinese medicine has shown therapeutic potential in treating osteoarthritis (OA) by regulating inflammation and maintaining cartilage homeostasis. However, the complex compositions of herbal medicines and the lack of efficient screening strategies have hindered the identification of active compounds and their molecular mechanisms. To address these challenges, this study used graph neural networks (GNNs) for drug discovery and demonstrated their potential in elucidating therapeutic mechanisms. Using an in-house GNN model, we identified Paederia scandens as a promising candidate for OA treatment. Experimental validation confirmed that Paederia scandens improved cartilage metabolic homeostasis and mitigated subchondral bone sclerosis. Further analysis implicated asperuloside, a major constituent of Paederia scandens , as a key bioactive compound contributing to these therapeutic effects. Transcriptomic profiling and protein-protein interaction network analysis identified Integrin Subunit Beta 1 as a potential central regulatory hub. Asperuloside treatment was found to reshape cartilage gene expression; downregulate cytokine and chemokine signaling pathways; and alleviate inflammation, while enhancing cartilage matrix synthesis and decreasing matrix degradation. Further in vivo and in vitro experiments consistently supported these findings. Collectively, our findings indicated that asperuloside is a promising OA therapeutic candidate. Moreover, the GNN-driven framework established in this study provides a novel strategy for modernizing traditional Chinese medicine and accelerating the discovery of bioactive compounds. This work highlights the critical role of GNNs in integrating computational prediction with biological validation to facilitate mechanistic exploration and advance precision drug development for complex diseases such as OA.

A metabolomics study was conducted on serum and liver samples from mice with alcoholic liver injury induced by the National Institute on Alcohol Abuse and Alcoholism(NIAAA). This was combined with network pharmacology to investigate the ameliorative effect of Tricholoma matsutake extracts on alcoholic liver injury in mice and its underlying mechanism. Serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), and triglyceride(TG) were measured, while liver pathological changes were assessed by hematoxylin-eosin(HE) staining. Moreover, differential metabolites in serum and liver were detected by gas chromatography-mass spectrometry(GC-MS), and potential targets of T. matsutake extracts were analyzed via network pharmacology. The predicted targets were compared with those associated with differential metabolites to explore key targets involved in the amelioration of alcoholic liver injury by the extract. The results showed that, compared with the pathological model group, the T. matsutake extracts treatment group showed significantly reduced serum ALT, AST, and TG levels, along with improved lipid vacuolation and hepatocyte morphology, indicating a significant ameliorative effect of the extract on alcoholic liver injury in mice. The metabolomics results revealed that the extract modulated 12 differential metabolites in liver tissues, including glucose, glutamate, leucine, and phenylalanine, and 31 differential metabolites in serum, including alanine, cholesterol, glucose, lactose, and methionine. Further network pharmacology analysis suggested that T. matsutake extracts may ameliorate alcoholic liver injury primarily by targeting pathways related to Myc and Cat, influencing genes such as Aldh9a1, Aldh3a2, Aldh2, Hsd17b4, Ehhadh, Acox1, Acaa1, Acot1, and Gls. These were mainly involved in five metabolic pathways: cysteine and methionine metabolism, arginine biosynthesis, and alanine, aspartate, and glutamate metabolism. In conclusion, T. matsutake extracts may ameliorate alcoholic liver injury in mice by regulating amino acid metabolism and glucose metabolism through pathways associated with Myc and Cat.

ABSTRACT Colorectal cancer (CRC) is one of the most common and lethal cancers globally, with early detection of precancerous lesions being crucial for reducing its incidence and mortality. Colorectal precancerous lesions, including adenomas, serrated lesions, and dysplasias associated with inflammatory bowel disease (IBD), represent key targets for preventive strategies. Despite advancements in screening and therapeutic options, medicinal natural products clinical application is frequently challenged by low bioavailability, complex in vivo metabolism, unclear adverse effects and side‐effect profiles, and a strong reliance on empirical standards in clinical use. This review provides a comprehensive overview of the definition, classification, and molecular mechanisms underlying colorectal precancerous lesions, epigenetic modifications, and genetic factors. It also highlights the application of multi‐omics technologies in understanding lesion heterogeneity. In addition, the review evaluates cutting‐edge research models such as organoids, 3D co‐culture systems, and various in vivo models, offering insights into their potential for studying CRC precursors. This review summarizes current mechanistic insights into early colorectal carcinogenesis and highlights three major translational directions: therapeutic strategies targeting key genomic alterations; immunologic modulation relevant to inflammation‐driven tumor initiation; and multi‐omics stratification optimizing dosing and patient selection. These perspectives outline emerging opportunities for developing more precise and clinically actionable preventive interventions.

Traditional Chinese Medicine (TCM) represents a multi-component therapeutic system with substantial chemical complexity. This complexity makes it difficult to directly elucidate anti-gastric cancer mechanisms from macroscopic herbal formulae. To support the systematic prioritization of potential small-molecule candidates, this study focuses on screening bioactive small-molecule constituents from TCM. We constructed a heterogeneous network integrating Chinese herbal pieces (CHPs), Chinese patent medicines (CPMs), genes, diseases, and small molecules, and incorporated metapath2vec representations and attention mechanisms into a graph neural network framework, the model is designed to learn relational patterns among heterogeneous nodes. Network pharmacology and in vitro validation in AGS and MKN-45 gastric cancer cell lines show that Icaritin and Arundine inhibit cell proliferation and induce apoptosis. This study presents an AI-assisted pipeline for candidate prioritization, providing methodological support for the systematic prioritization and preliminary validation of bioactive TCM molecules in gastric cancer.