Dysregulation of the KLF9/TXNRD2 Axis Leads to Mitochondrial DNA Oxidation and NLRP3 Inflammasome Activation in Ulcerative Colitis.

Authors

Yijia Fan, Lingling Dai, Feng Zhu, Mingfang Ping, Xiaofeng Zhu, Junguo Chen

Published in

Journal of biochemical and molecular toxicology. Volume 40. Issue 9. Pages e71074.

Abstract

This study investigated the roles and mechanism of the transcription factor KLF9 and its downstream target gene TXNRD2 in ulcerative colitis (UC). An in vitro inflammatory model was established by stimulating human normal colonic mucosal epithelial cells (NCM460) with LPS and ATP. KLF9 or TXNRD2 expression was knocked down using RNA interference, and rescue experiments were performed using the NLRP3-specific agonist nigericin or by co-transfection with si-TXNRD2. A 3% DSS-induced UC model was established in C57BL/6 mice. Interventions were performed by tail vein injection of sh-KLF9 adeno-associated virus and/or intraperitoneal injection of nigericin. In DSS-induced UC mouse colon tissues and LPS/ATP-stimulated NCM460 cells, KLF9 was upregulated. KLF9 directly bound to the TXNRD2 promoter. Silencing KLF9 restored TXNRD2 expression, alleviated LPS/ATP-induced oxidative stress, decreased the accumulation of cytoplasmic ox-mtDNA and mtDNA, and inhibited NLRP3 inflammasome activation, as well as reduced pyroptosis, LDH release, and pro-inflammatory cytokine secretion. si-TXNRD2 or nigericin partially reversed the protective effects of KLF9 silencing. Colon-specific KLF9 knockdown improved DSS-induced weight loss, colonic shortening, disease activity index, and histopathological damage in mice, while simultaneously upregulating TXNRD2, inhibiting the NLRP3 pathway, and reducing oxidative stress and cytoplasmic mtDNA accumulation. Nigericin intervention partially offset the protective effects of KLF9 knockdown. KLF9 suppresses TXNRD2 transcription, leading to increased mitochondrial oxidative stress and the release of ox-mtDNA in intestinal epithelial cells, which in turn triggers NLRP3 inflammasome activation, driving pyroptosis and intestinal inflammation.

PMID:
42635086
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.

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