Overcoming primary non-response to infliximab in ulcerative colitis: monocyte-derived PTGS2 as a therapeutic target
- 1Key Laboratory of Digestive Diseases, The Second Hospital and Clinical Medical School, Lanzhou University
- 2Department of Gastroenterology, The Second Hospital and Clinical Medical School, Lanzhou University
- 3MeDiC Program, The Research Institute of McGill University Health Centre and Division of Endocrinology and Metabolism, Department of Medicine, McGill University
Abstract
Background: Primary non-response (PNR) to infliximab (IFX) remains a major therapeutic challenge in ulcerative colitis (UC). However, the molecular mechanisms underlying this treatment failure remains unelucidated. Therefore, there is an urgent need to identify the key drivers of PNR and develop effective interventions to improve therapeutic outcomes.
Methods: Human colonic RNA-sequencing data were analyzed to identify molecular features associated with PNR to IFX. Immune infiltration analysis, clinical sample validation, virtual gene knockout, and single-cell RNA sequencing were performed to characterize the immune landscape, identify the key regulatory molecule, and elucidate its underlying mechanisms and cellular source. Network pharmacology and molecular docking were employed to identify a potential therapeutic strategy targeting the key regulatory molecule, followed by mechanistic and functional validation in cell-based assays and therapeutic evaluation in a DSS-induced murine colitis model.
Results: Excessive colonic neutrophil infiltration marked PNR in UC prior to IFX treatment. PTGS2 positively correlated with neutrophil infiltration and was predominantly expressed in colonic CD14 ⁺ S100A9 ⁺ inflammatory monocytes. Virtual knockout of PTGS2 altered genes related to neutrophil chemotaxis, which were primarily enriched in the NF-κB signaling axis. Gegen Qinlian Decoction (GQD), a traditional Chinese herbal formula, was identified to target PTGS2 through multiple bioactive constituents, with quercetin exhibiting the highest binding affinity. Quercetin suppressed LPS-induced PTGS2 expression in inflammatory monocytes, thereby inhibiting the NF-κB/CXCL8 signaling and attenuating neutrophil chemotaxis, as further supported by PTGS2 knockdown and overexpression experiments. In vivo , GQD markedly reduced PTGS2 expression and neutrophil accumulation in the inflamed colon, thereby significantly ameliorating disease severity and enhancing IFX responsiveness in DSS-induced colitis.
Conclusion: Monocyte-derived PTGS2 contributes to primary IFX non-response by promoting neutrophil recruitment in UC. GQD improves IFX responsiveness by suppressing PTGS2-associated inflammatory signaling and neutrophil recruitment, highlighting its potential as a therapeutic strategy to enhance IFX efficacy.
Related
- Biopsy-Based Molecular Signatures Predicting Therapeutic Response in Ulcerative Colitis
- Upadacitinib as a rescue therapy for steroid- and infliximab-refractory acute severe ulcerative colitis: short- and long-term effectiveness and safety in a multicenter cohort study
- Associations between redox-related biomarkers and treatment response in patients with inflammatory bowel disease initiating infliximab or vedolizumab
- Longitudinal Metaproteomic and Lysine Crotonylation Remodeling Defines Clinical Response to Fecal Microbiota Transplantation in Ulcerative Colitis
- Extrachromosomal DNA: A New Therapeutic Frontier for Overcoming Cancer Drug Resistance
BibTeX
@article{pu2026overcoming,
title = {{Overcoming primary non-response to infliximab in ulcerative colitis: monocyte-derived PTGS2 as a therapeutic target}},
author = {Dan Pu and Xiaojuan Kang and Lingzhu Gou and Xiaoli Li and Pengfei Wang and Guoqing Qi and Jun-Li Liu and Dekui Zhang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1957588},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957588/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Overcoming primary non-response to infliximab in ulcerative colitis: monocyte-derived PTGS2 as a therapeutic target
AU - Dan Pu
AU - Xiaojuan Kang
AU - Lingzhu Gou
AU - Xiaoli Li
AU - Pengfei Wang
AU - Guoqing Qi
AU - Jun-Li Liu
AU - Dekui Zhang
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1957588
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957588/full
AB - Background: Primary non-response (PNR) to infliximab (IFX) remains a major therapeutic challenge in ulcerative colitis (UC). However, the molecular mechanisms underlying this treatment failure remains unelucidated. Therefore, there is an urgent need to identify the key drivers of PNR and develop effective interventions to improve therapeutic outcomes. Methods: Human colonic RNA-sequencing data were analyzed to identify molecular features associated with PNR to IFX. Immune infiltration analysis, clinical sample validation, virtual gene knockout, and single-cell RNA sequencing were performed to characterize the immune landscape, identify the key regulatory molecule, and elucidate its underlying mechanisms and cellular source. Network pharmacology and molecular docking were employed to identify a potential therapeutic strategy targeting the key regulatory molecule, followed by mechanistic and functional validation in cell-based assays and therapeutic evaluation in a DSS-induced murine colitis model. Results: Excessive colonic neutrophil infiltration marked PNR in UC prior to IFX treatment. PTGS2 positively correlated with neutrophil infiltration and was predominantly expressed in colonic CD14 ⁺ S100A9 ⁺ inflammatory monocytes. Virtual knockout of PTGS2 altered genes related to neutrophil chemotaxis, which were primarily enriched in the NF-κB signaling axis. Gegen Qinlian Decoction (GQD), a traditional Chinese herbal formula, was identified to target PTGS2 through multiple bioactive constituents, with quercetin exhibiting the highest binding affinity. Quercetin suppressed LPS-induced PTGS2 expression in inflammatory monocytes, thereby inhibiting the NF-κB/CXCL8 signaling and attenuating neutrophil chemotaxis, as further supported by PTGS2 knockdown and overexpression experiments. In vivo , GQD markedly reduced PTGS2 expression and neutrophil accumulation in the inflamed colon, thereby significantly ameliorating disease severity and enhancing IFX responsiveness in DSS-induced colitis. Conclusion: Monocyte-derived PTGS2 contributes to primary IFX non-response by promoting neutrophil recruitment in UC. GQD improves IFX responsiveness by suppressing PTGS2-associated inflammatory signaling and neutrophil recruitment, highlighting its potential as a therapeutic strategy to enhance IFX efficacy.
SN - 1664-3224
ER -