ObjectivePhosgene is a highly toxic asphyxiating gas and also an important chemical raw material. Phosgene has been regarded as an environmental pollutant, and the accidental leakage of phosgene in the process of industrial production has posed a serious threat to related occupational groups. Phosgene exposure may lead to acute lung injury (ALI), marked by inflammation, heightened vascular permeability, and potentially life-threatening pulmonary edema. BML-111 is a lipid A4 receptor agonist which is compound with anti-inflammatory and antioxidant properties. The involvement of BML-111 in mitigating phosgene-induced ALI and the underlying mechanisms remain unclear.MethodsIn this study, we established a phosgene induced ALI rat model, examined the effects of phosgene exposure on lung tissue and bronchoalveolar lavage fluid (BALF) of rats, and evaluated the lung tissue pathology, lung wet weight, lung coefficient and respiratory function of phosgene exposed rats after intervention with BML-111. The levels of pro-inflammatory cytokines and oxidative stress markers were measured in BALF and lung tissue.ResultsThis study showed that BML-111 notably enhanced respiratory function, mitigated ALI severity, and reduced pulmonary edema in phosgene-exposed rats. Mechanistically, these protective effects were attributed to a reduction in pro-inflammatory cytokines and oxidative stress, alongside an enhancement of overall antioxidant capacity. Furthermore, it was found that the activation of ACE2 is a key mechanism through which BML-111 exerts its protection.ConclusionThe findings suggest that BML-111 can alleviate phosgene-induced ALI in rats by activating ACE2, thereby inhibiting inflammatory responses and oxidative stress. BML-111 shows promise as a preventive candidate for treating phosgene-induced ALI.

Oncolytic virus M1 (OVM), currently in phase 1/2 clinical trials, is a single-stranded, positive-sense RNA virus. However, the host factors that engage its viral RNA to govern viral replication and oncolytic efficacy remain largely unknown. Here, by using RNA affinity purification coupled with mass spectrometry and CRISPR-Cas9 screening, we identify Y-box binding protein 1 (YBX1) as a predominant proviral RNA-binding protein. Functional dissection reveals that the cold shock domain of YBX1, specifically its aromatic residues W65, F74, and F85, are essential for binding OVM RNA and sustaining viral replication. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing maps that YBX1 binds to conserved sequence elements at the NSP4-capsid junction and 3' UTRs that function as promoters for viral RNA synthesis. Consequently, loss of YBX1 severely impairs viral RNA synthesis. This molecular dependency translates to a profound functional effect: across multiple tumor models, YBX1 deficiency abrogates OVM replication and oncolytic activity, while re-expression restores both. Importantly, YBX1 expression levels not only correlate with cellular susceptibility to OVM in cancer cell lines and ex vivo tumors but are also elevated in several human malignancies. Collectively, these findings establish YBX1 as a master regulator of OVM replication and a predictive biomarker for its therapeutic efficacy.

Autophagy is a conserved catabolic pathway essential for maintaining cellular integrity, recycling damaged organelles, and supporting metabolic adaptation during stress. Beyond its homeostatic functions, aberrant autophagy plays a critical role in cancer initiation and progression. Once viewed primarily as a tumor-suppressive mechanism linked to programmed cell death, autophagy is now recognized as a highly context-dependent process that can either inhibit or facilitate tumor development. Growing evidence demonstrates that autophagy regulates multiple cancer hallmarks, including metastasis, sustained proliferation, therapeutic resistance, and immune regulation. In this review, we explore how autophagy intersects with the immune system to remodel the tumor microenvironment (TME), highlighting its dual and often paradoxical roles. Autophagy shapes the activation, differentiation, and effector functions of both innate and adaptive immune cells, enhancing antitumor immunity while also promoting immune evasion. Major TME constituents, such as tumor-associated macrophages, cancer-associated fibroblasts, dendritic cells, natural killer cells, and cytotoxic T lymphocytes, undergo autophagy-dependent reprogramming, particularly in response to hypoxia, nutrient stress, and inflammatory cues. Notably, autophagy-driven immunogenic cell death has emerged as a promising avenue to augment cancer immunotherapies, including immune checkpoint inhibitors and adoptive cell therapies. Recent preclinical and clinical advances targeting autophagy pathways underscore new therapeutic opportunities and position autophagy modulators as emerging immunopharmacological agents. Elucidating how autophagy-mediated immune remodeling shapes the TME may enable the development of next-generation precision cancer therapies.

In vitro gut microbiome-culturing models are essential for studying host-microbe interactions, yet achieving high microbial recovery and long-term stability remains a long-standing challenge. Here we devise X-Gutor, an ecologically designed in vitro platform that recapitulates the monogastric digestive system with precise control of pH, redox potential, and a mucin-based biofilm matrix. Using an integrated assessment framework, microbial source tracking, a curated gut metabolism database (GutDB), and short-chain fatty acid profiling, we benchmarked gut community recovery. Building on this platform, HanGutor and PigGutor were developed to recover 96.27±4.92% and 90.48±5.95% of human and swine gut microbiota, respectively. Ecological fine-tuning revealed that redox potential drives the Prevotella-Bacteroides trade-off and that spatial biofilm structure suppresses cheater (Succinivibrio) growth. The X-Gutor provides a scalable, modular platform for gut microbiome engineering, dietary intervention, and microbiota-targeted therapy development.

Background Oncolytic virus M1 encoding a mutant IL-18 decoy (OVM18) represents a novel virotherapy that integrates selective oncolysis with localized activation of the IL-18 pathway. However, the heterogeneity of therapeutic responses suggests that host immune determinants influence its efficacy. Methods To elucidate these determinants, we performed integrated immune profiling using bulk and single-cell transcriptomics, flow cytometry, and T cell receptor (TCR) repertoire analyses. The functional contribution of specific immune subsets was validated using Batf3⁻/⁻ mice and FTY720-mediated lymphocyte trafficking blockade. Potential synergistic immunotherapies were identified through transcriptomic database screening and confirmed in tumor-bearing mice receiving combined OVM18 and immune checkpoint blockade. Results We identified intratumoral IL-18R1 + CD8 + T cells as an important effector population, whose IL-18R1 expression and intratumoral abundance positively correlate with OVM18 efficacy. Integrated single-cell RNA-sequencing and cytometry analyses revealed that IL-18R1 + CD8 + T cells are clonally expanded, tumor antigen-enriched, polyfunctional cytotoxic T cells. Their generation requires conventional type 1 dendritic cells (cDC1)-dependent priming within tumor-draining lymph nodes, followed by trafficking into tumors to mediate antitumor responses. Notably, CTLA-4 blockade enhances cDC1-derived IL-12 and promotes IL-18R1 + CD8 + T-cell expansion, thereby overcoming resistance to OVM18 therapy. Combination treatment with OVM18 and anti-CTLA-4 enhances intratumoral IL-18R1 + CD8 + T cell infiltration, delays tumor progression, and prolongs survival in poor-responsive models. Conclusions Our findings establish IL-18R1 + CD8 + T cells as an important effector population in OVM18 therapy, thereby providing a strong rationale for combining OVM18 with CTLA-4 blockade to overcome therapeutic resistance and achieve durable antitumor responses.

Oncolytic virus M1 is a promising anticancer agent; however, its therapeutic efficacy is often limited by insufficient intratumoral viral replication and host antiviral immunity. Sirolimus, an mTOR inhibitor widely used in transplantation immunosuppression, has demonstrated potential to modulate antiviral responses. This study investigates whether sirolimus potentiates the efficacy of M1 virotherapy and elucidates the underlying mechanisms. Sirolimus significantly enhanced the antitumor efficacy of M1 virus in murine prostate cancer and liver cancer models, leading to reduced tumor growth. This synergistic effect remained evident in CD8⁺ T cell-depleted mice, indicating that the therapeutic benefit is independent of adaptive cytotoxic immunity. Mechanistically, sirolimus markedly increased M1 viral replication in tumor tissues, accompanied by enhanced tumor cell-cycle arrest and apoptosis. Notably, sirolimus selectively amplified viral load within tumors but not in normal organs, demonstrating tumor-specific viral enrichment and safety. Further analyses revealed that this increase in intratumoral virus was driven by mTOR pathway inhibition rather than alterations in macrophage or NK cell populations. Transcriptomic profiling and molecular validation indicated that sirolimus-mediated mTOR suppression downregulated key type I interferon-stimulated genes (Ifitm1, Stat1, Ifit3), thereby attenuating intrinsic antiviral defenses and facilitating viral amplification. In summary, sirolimus potentiates M1 oncolytic virotherapy by selectively enhancing viral replication in tumors via mTOR inhibition and suppression of type I interferon signaling, independent of CD8⁺ T cell-mediated immunity. These findings establish a mechanistic rationale for combining mTOR inhibitors with oncolytic viruses to achieve dual benefits of enhanced viral oncolysis and controlled immunosuppression, with translational relevance for cancer patients requiring long-term immunosuppressive therapy.

Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in cancer patients, commonly treated with low-molecular-weight heparin (LMWH). LMWH is structurally similar to cell-surface heparan sulfate (HS), a key mediator of viral attachment, raising concerns that anticoagulation might interfere with oncolytic virotherapy. Here, we found that heparin directly binds oncolytic virus M1 (OVM). While high-dose enoxaparin inhibited viral infection, clinically relevant plasma concentrations (0.52-1.2 IU/mL) unexpectedly enhanced OVM infection and oncolysis in human bladder cancer cells. Mechanistically, enoxaparin at these concentrations facilitates viral attachment via HS proteoglycans (HSPGs). Crucially, this potentiation depends on the host innate immune landscape and is restricted to cells with attenuated interferon-α (IFN-α) responses. In vivo, clinically relevant enoxaparin significantly enhanced the antitumor efficacy of OVM without added toxicity, highlighting a novel and feasible strategy to potentiate oncolytic virotherapy using a standard anticoagulant in bladder cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Increasing evidence has shown that ferroptosis plays a significant regulatory role in the occurrence and progression of cancer. However, new biomarkers associated with ferroptosis and new ferroptosis-related subtypes in CRC remain to be identified. We collected a colon adenocarcinoma (COAD) dataset from the cancer genome atlas (TCGA) database in UCSC Xena. Ferroptosis-related genes (FRGs) were extracted from the dataset, and we conducted gene expression profiling interactive analysis (GEPIA), cBioPortal analysis, and immune cell infiltration analysis. Additionally, we used the "ConsensusClusterPlus" R package to identify ferroptosis-related subtypes of CRC. Based on these subtypes, we analyzed their prognostic features, gene co-expression networks, and the ferroptosis landscape. We identified 21 FRGs in COAD. The genes RBMS1, NOX4, FABP4, CYB5R1, CPEB1, and ATM were significantly and positively correlated with immune cell infiltration and poor prognosis. Furthermore, we identified two COAD subtypes related to prognosis and ferroptosis (ferroptosis subtype 1 [FS1] and ferroptosis subtype 2 [FS2]). These subtypes were associated with tumor mutation burden (TMB), mutation status, immunogenic cell death (ICD), and immune checkpoint (ICP) regulatory genes. Finally, we established a ferroptosis landscape of COAD. We identified key ferroptosis-related genes and defined two distinct ferroptosis-associated subtypes in CRC that differ significantly in prognosis and immune infiltration. These findings provide new insights into the interaction between ferroptosis and the tumor immune microenvironment, offering potential biomarkers and therapeutic targets for improved diagnosis and personalized treatment of colorectal cancer.

Viral receptors are essential host factors that determine the tropism of oncolytic viruses, and contribute to their selective targeting of cancer cells. In this study, a membrane protein-targeted CRISPR-Cas9 screen is conducted and identify transmembrane protein adipocyte-associated 1 (TPRA1) as a novel receptor for oncolytic virus M1(OVM), a promising oncolytic virus currently under clinical investigation. Mechanistically, TPRA1 facilitates OVM infection by promoting both viral attachment and internalization. Extracellular region of TPRA1 directly binds OVM particles via glycosylation, while its cytoplasmic tail mediates virus endocytosis, collectively enabling efficient viral entry and cancer cell lysis. Importantly, TPRA1 expression in cell lines, mouse models, and patient-derived tumor samples are positively correlated with their respective sensitivity to OVM, and TPRA1 is upregulated in a high proportion of tumors compared to adjacent normal tissues, highlighting its potential as a therapeutic response biomarker. Furthermore, TPRA1 also promotes the entry of Semliki Forest Virus, suggesting its conserved role in alphavirus infection. Together, these findings establish TPRA1 as both a mechanistic determinant of OVM tropism and a biomarker to guide patient selection in clinical trials of OVM-based therapy.

OBJECTIVES:Difficult-to-treat Crohn's disease (DTT-CD) represents a critical unmet need in inflammatory bowel disease (IBD) management. However, its genetic architectures remain poorly understood. We aimed to evaluate the genetic characteristics and clinical manifestations of DTT-CD cases through integrated trio-based whole exome sequencing (WES) and longitudinal phenotyping. METHODS:In this cross-sectional cohort study, DTT-CD patients who met the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) criteria and their first-degree relatives underwent trio-WES analysis. Treatment persistence and remission rates were analyzed. Genetic variants were prioritized via cosegregation analysis, the American College of Medical Genetics and Genomics (ACMG) guidelines, and functional prediction algorithms. RESULTS:Among the 24 patients with DTT-CD, 87.5% failed at least two biologics, 33.3% required dual targeted therapy, and drug persistence declined across treatment lines (p = 0.0193). Remission rates were suboptimal (clinical: 41.7%; endoscopic: 50.0%). Trio-WES analysis identified 15 likely pathogenic candidate variants across 12 genes, including the established monogenic IBD gene XIAP (two novel variants: p.Asp247Glufs*19, p.Ser43X; two known variants: p.Arg381X, p.Arg238X), genome-wide association studies-implicated IBD risk genes (MAML2 and PLA2R1), and novel candidate variants (KIZ, LAMA5, SAMD9, etc.) that were potentially linked to epithelial-immune dysregulation. CONCLUSIONS:This is the first trio-WES study of DTT-CD that reveals a high prevalence of monogenic XIAP deficiency (16.7%), advocating for genetic screening in refractory cases. Novel candidate genes implicate polygenic mechanisms of therapeutic resistance. Family-based sequencing may be used to elucidate the genetic background of DTT-CD cases to guide molecular diagnosis and personalized therapy.

Conflicting results have been reported on dietary factors in inflammatory bowel diseases (IBDs). Here, we compared the dietary intakes of IBD patients with those of paired healthy relatives (HRs), aiming to minimize the impact of genetic and environmental confounders. Patients with Crohn’s disease (CD, N = 45) and ulcerative colitis (UC, N = 20), their paired HRs (NCD−HR = 45, NUC−HR = 20) and healthy non-relative (HNR, NCD−HNR = 25, NUC−HNR = 55) controls were recruited. Participants have kept dietary habits since the onset of IBDs and report no other recent digestive diseases or surgeries. Pre-illness dietary factors were assessed through 24-hour recall interviews. Statistical analyses included Analysis of Variance, Fisher’s exact tests, Wilcoxon rank sum tests, logistic regressions, Area Under the Receiver-Operator Curve (AUROC) analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression. Dietary features identified in IBD patients using the HR controls differed from those identified using the HNR controls. For CD, lower intakes of vitamin C, dietary fiber, calcium, vegetables, decanoic acid (10:0), milk, dairy foods, and β-carotene were identified as risk factors when compared to HRs. LASSO regression highlighted milk, vegetables, and vitamin C as the most significant risk factors for CD. In UC patients, lower intakes of phosphorus, docosapentaenoic acid (DPA, 22:5, n-3), vitamins B-2 and B-12, and choline, along with a higher intake of α-carotene, were identified as risk factors compared to HRs. LASSO regression emphasized DPA, vitamins B-2 and B-12, and α-carotene as the most significant risk factors for UC. Monitoring dietary intake patterns is crucial for the prevention and personalized treatment of CD and UC.

Achieving a cure is an urgent need for patients with advanced solid tumors. Here, we discover that oncolytic virus (OV) infection enhances IL-18 receptor expression but fails to increase IL-18 ligand expression. Therefore, we engineer armed oncolytic alphavirus M1 expressing wild-type IL-18 (wtIL-18) or a mutant variant (mutIL-18) that evades IL-18 binding protein (IL-18BP) while maintaining IL-18 receptor (IL-18R) binding. Intravenous administration of M1-mutIL-18 suppresses the growth of multiple advanced solid tumors in C57BL/6 and BALB/c mouse models and promotes long-term systemic immune memory. Mechanistically, armed M1-mutIL-18 enhances directed clonal expansion and differentiation of CD8+ T cells and sustains IFN-γ production. Thus, armed M1-mutIL-18 promotes dendritic cell (DC) activation, priming and activation of CD8+ T cells in lymphatic organs, and infiltration of IL-18R+ CD8+ T cells in the tumor microenvironment, establishing a positive feedback loop. We further show that a PD-L1 inhibitor enhances the anti-tumor efficacy of mutIL-18 OVs. These results highlight the importance of the IL-18 pathway in oncolytic virus therapy and implicate reprogramming ligand-receptor interaction as an effective strategy for immunotherapy.

The impact of coronavirus disease 2019 (COVID-19) history on Crohn’s disease (CD) is unknown. This investigation aimed to examine the effect of COVID-19 history on the disease course, oral-gut microbiota, and serum metabolomics in patients with CD. In this study, oral-gut microbiota and serum metabolomic profiles in 30 patients with CD and a history of mild COVID-19 (positive group, PG), 30 patients with CD without COVID-19 history (negative group, NG), and 60 healthy controls (HC) were assessed using 16S rDNA sequencing and targeted metabolomics. During follow-up, the CD activity index showed a stronger decrease in the PG than in the NG (p = 0.0496). PG patients demonstrated higher α-diversity and distinct β-diversity clustering in both salivary and fecal microbiota compared to NG and HC individuals. Notably, the gut microbiota composition in the PG patients showed a significantly greater similarity to that of HC than NG individuals. The interaction between oral and intestinal microbiota in the PG was reduced. Moreover, serum metabolome analysis revealed significantly increased anti-inflammatory metabolites, including short-chain fatty acids and N-Acetylserotonin, among PG patients; meanwhile, inflammation-related metabolites such as arachidonic acid were significantly reduced in this group. Our data suggest that the gut microbiota mediates a potential beneficial effect of a mild COVID-19 history in CD patients.

Imbalanced dietary intake is common in patients with inflammatory bowel diseases (IBD). Studies on pre-illness dietary intake identified risk and protective food groups and nutrients. Based on these findings, the American Gastroenterological Association states that patients with IBD will benefit from a diet rich in a variety of fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins while being low in ultraprocessed foods, added sugar, and salt. Malnutrition is common in IBD, especially Crohn’s disease. Nutritional therapies were initiated to improve the nutritional status of the patients, and happen to induce remission in many patients. However, nutritional interventions may achieve better outcomes by incorporating the findings on the dietary risk and protective factors for IBD.

Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and Cmax, and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

AbstractResistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune checkpoint PD-L1, was combined with the oncolytic virus M1 (OVM1) to treat mice with either prostate cancer (RM-1) or glioma (GL261) tumors. This combination therapy enhanced anti-tumor effects in immunocompetent mice, but not in immunodeficient fi cient ones, without increasing OVM1 replication. Instead, it led to an increase in the number of CD8+ + T cells within the tumor, down regulated the expression of PD1 on CD8+ + T cells, and upregulated activation markers such as Ki67, CD44, and CD69 and the secretion of cytotoxic factors including interferon (IFN)-g, g granzyme B, and tumor necrosis factor (TNF)-a. a . Consistently, it enhanced the in vitro tumor-killing activity of lymphocytes from tumor-draining lymph nodes or spleens. The synergistic effect of Albendazole on OVM1 was abolished by depleting CD8+ + T cells, suggesting a CD8+ + T cell-dependent mechanism. In addition, Albendazole and OVM1 therapy increased CTLA4 expression in the spleen, and the addition of CTLA4 antibodies further enhanced the anti-tumor efficacy fi cacy in vivo. In summary, Albendazole can act synergistically with oncolytic viruses via CD8+ + T cell activation, and the Albendazole/OVM1 combination can overcome resistance to CTLA4-based immune checkpoint blockade therapy.

Wu et al.[1]recently published a study on potential prognostic and therapeutic values of immune cell infiltration(ICI)subtypes in colorectal cancer(CRC).In this study,they creatively designed a new approach combining the CIBERSORT and ESTIMATE meth-ods to assess the differences in the intra-tumor immune infiltra-tion landscape of CRC samples and its association with prognosis.

Microorganisms play an important role in the pathogenesis of inflammatory bowel disease (IBD). The oral cavity, the second-largest microbial niche, is connected to the gastro-intestinal tract. Ectopic gut colonization by oral microbes is a signature of IBD. Current studies suggest that patients with IBD often report more oral manifestations and these oral issues are closely linked with disease activity. Murine studies have indicated that several oral microbes exacerbate intestinal inflammation. Moreover, intestinal inflammation can promote oral microbial dysbiosis and the migration of oral microbes to the gastro-intestinal tract. The reciprocal consequences of oral microbial dysbiosis and IBD, specifically through metabolic alterations, have not yet been elucidated. In this review, we summarize the relationship between oral bacteria and IBD from multiple perspectives, including clinical manifestations, microbial dysbiosis, and metabolic alterations, and find that oral pathogens increase anti-inflammatory metabolites and decrease inflammation-related metabolites.

Background:The genetic variant of tumor necrosis factor superfamily member 15 (TNFSF15) is associated with Crohn's disease (CD) and the development of intestinal fibrosis and stricturing. We aimed to investigate its predictive role in disease progression and the impact of ileal fibrosis-associated protein expression in Chinese patients with CD. Methods:We genotyped the single nucleotide polymorphism rs6478109 within the TNFSF15 gene in 428 CD patients and 450 health controls to assess its association with CD. Genotype-phenotype correlation analyses were performed. Mucosal samples from non-diseased terminal ileum were analyzed for TL1A and fibrosis-associated protein expression using western blot and immunohistochemistry. Results:The G allele frequency of rs6478109 was significantly higher among CD patients compared with health controls (63.3% vs. 46.7%, P < 0.001). Patients with GG genotype were more predisposed to develop the stricturing phenotype, compared with those with AA + AG genotypes with a hazard ratio of 1.426 (95% confidence interval: 1.029-1.977, P = 0.033). This trend was similarly observed in patients utilizing biological agents, with a hazard ratio of 4.396 (95% confidence interval: 1.780-10.854, P = 0.001). Furthermore, increased TL1A, pro-fibrotic proteins, and TGFβ1/Smad3 pathway activation were observed in non-diseased ileal mucosa of patients with GG genotype compared with those with AA genotype. Conclusions:The TNFSF15 risk genotype GG could promote the expression of pro-fibrotic proteins and may serve as a predictor for stricturing CD.