Linagliptin Mitigates DMH‐Induced Colorectal Cancer in Rats: Crosstalk Between NFAT and IL‐6/JAK2/STAT3/NF‐κB Signaling Hubs

Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer‐related deaths globally. Linagliptin is a dipeptidyl peptidase‐4 (DPP‐4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti‐inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2‐dimethylhydrazine (DMH)‐induced CRC via modulation of NFAT‐mediated IL‐6 and JAK2/STAT3/NF‐κB signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8‐week duration. Twenty‐four Wistar rats were segregated into three groups of eight rats each; normal control, DMH‐induced CRC and DMH + linagliptin (10 mg/kg; p.o). Linagliptin attenuated DMH‐induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF‐κB) induced by DMH which is highlighted using immunohistochemistry analysis. The anti‐inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T‐cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin‐6 (IL‐6) and cyclooxygenase‐2 (COX‐2) levels. Linagliptin mitigate the protein expression of DMH‐activated oncogenic janus‐activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B‐cell lymphoma 2 (Bcl‐2) and a significant elevation in Bcl‐2‐associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT‐mediated IL‐6 with JAK2/STAT3/NF‐κB signaling cascades.

• Publication year

  2025

• Venue

  Journal of biochemical and molecular toxicology

• Publication date

  2025-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/jbt.70206PMID 40070168
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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