The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments
9 affiliations
- 1Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
- 2Nanshan School, Guangzhou Medical University
- 3Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital
- 4The Third School of Clinical Medicine, Guangzhou Medical University
- 5Department of Otorhinolaryngology, The Seventh Affiliated Hospital of Sun Yat-Sen University
- 6Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital
- 7The Sixth School of Clinical Medicine, The Affiliated Qingyuan HospitaI (Qingyuan PeopIe’s HospitaI), Guangzhou Medical University
- 8Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University
- 9Department of Head and Neck Surgery, Sir Run Run Shaw Hospital, Zhejiang University
Abstract
Background: Emerging evidence highlights the anti-tumor properties of Glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their synergistic potential with standard chemotherapy remains largely unexplored.
Methods: Data from Genome-wide association study (GWAS) were used to select single-nucleotide polymorphisms (SNPs) strongly associated with lipid-lowering drug targets as instrumental variables. Causal effects were assessed primarily using the inverse variance weighted (IVW) method, supported by comprehensive sensitivity analyses to control for pleiotropy and heterogeneity. These Mendelian randomization (MR) findings were further validated through in vitro functional assays (cell viability, apoptosis, and Western blot) and an in vivo tumor-bearing mouse model.
Results: Glucagon-like peptide-1 receptor (GLP-1R) activity showed a significantly positive causal relationship with dihydrofolate reductase (DHFR; β = 0.323, P = 6.02 × 10 ⁻¹⁷ ) and apoptosis regulator Bcl-2 (β = 0.259, P = 2.1 × 10 ⁻¹¹ ) but a negative relationship with ribonucleoside-diphosphate reductase large subunit (RRM1; β = −0.12, P = 2.32 × 10 ⁻³ ). Functional experiments validated these genetic findings. GLP-1RA significantly enhanced the antitumoral efficacy of gemcitabine both in vitro and in vivo by repressing RRM1. Conversely, GLP-1RA attenuated the anti-tumor effects of methotrexate and paclitaxel by upregulating DHFR and Bcl-2, respectively. Notably, GLP-1RA combination therapy achieved these modulatory effects without exacerbating chemotherapy-associated systemic toxicity.
Conclusion: GLP1-RAs can influence the efficacy of chemotherapeutic drugs such as methotrexate, paclitaxel, and gemcitabine.
Related
- Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists
- Context-dependent pharmacological effects of GLP-1 receptor agonists in breast cancer from molecular mechanisms to clinical safety
- Association of GLP-1 Receptor Agonists, SGLT 2 Inhibitors, DPP-4 Inhibitors, and Sulfonylureas with Incident Cancer in Type 2 Diabetes
- Transition Intermediates Encode Ligand Efficacy at the μ-Opioid Receptor-Gi Protein Complex
- Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy regulation
BibTeX
@article{huang2026impact,
title = {{The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments}},
author = {Sha Huang and Yongqi Feng and Yeling Liu and Xiaochun Mo and Haichuan Hu and Haolin Chen and Mengyi Han and Wanting Huang and Wantong Zheng and Xinting Hou and Runfeng Wen and Chenbing Liu and Jiahui Wang and Yunzhen Wang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1957757},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1957757/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments
AU - Sha Huang
AU - Yongqi Feng
AU - Yeling Liu
AU - Xiaochun Mo
AU - Haichuan Hu
AU - Haolin Chen
AU - Mengyi Han
AU - Wanting Huang
AU - Wantong Zheng
AU - Xinting Hou
AU - Runfeng Wen
AU - Chenbing Liu
AU - Jiahui Wang
AU - Yunzhen Wang
PY - 2026
DA - 2026/10/23
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1957757
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1957757/full
AB - Background: Emerging evidence highlights the anti-tumor properties of Glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their synergistic potential with standard chemotherapy remains largely unexplored. Methods: Data from Genome-wide association study (GWAS) were used to select single-nucleotide polymorphisms (SNPs) strongly associated with lipid-lowering drug targets as instrumental variables. Causal effects were assessed primarily using the inverse variance weighted (IVW) method, supported by comprehensive sensitivity analyses to control for pleiotropy and heterogeneity. These Mendelian randomization (MR) findings were further validated through in vitro functional assays (cell viability, apoptosis, and Western blot) and an in vivo tumor-bearing mouse model. Results: Glucagon-like peptide-1 receptor (GLP-1R) activity showed a significantly positive causal relationship with dihydrofolate reductase (DHFR; β = 0.323, P = 6.02 × 10 ⁻¹⁷ ) and apoptosis regulator Bcl-2 (β = 0.259, P = 2.1 × 10 ⁻¹¹ ) but a negative relationship with ribonucleoside-diphosphate reductase large subunit (RRM1; β = −0.12, P = 2.32 × 10 ⁻³ ). Functional experiments validated these genetic findings. GLP-1RA significantly enhanced the antitumoral efficacy of gemcitabine both in vitro and in vivo by repressing RRM1. Conversely, GLP-1RA attenuated the anti-tumor effects of methotrexate and paclitaxel by upregulating DHFR and Bcl-2, respectively. Notably, GLP-1RA combination therapy achieved these modulatory effects without exacerbating chemotherapy-associated systemic toxicity. Conclusion: GLP1-RAs can influence the efficacy of chemotherapeutic drugs such as methotrexate, paclitaxel, and gemcitabine.
SN - 1663-9812
ER -