Ref-1 drives ulcerative colitis induced systemic defects in hematopoietic cells

  • Commun Biol. 2026 Mar 19. doi: 10.1038/s42003-026-09860-z.
Ramesh Kumar  1 ,  Rahul Kanumuri  1 ,  Sarah S Burns  1 ,  Baskar Ramdas  1 ,  Lakshmi Reddy Palam  1 ,  Santhosh Kumar Pasupuleti  1 ,  Xuepeng Wang  1 ,  Rajaraman Eri  2 ,  Kulmira Nurgali  3 ,  Mark R Kelley  1 ,  Reuben Kapur  4
Affiliations
  • 1. Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 2. School of Science, STEM College, RMIT University, Melbourne, VIC, Australia.
  • 3. Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
  • 4. Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
PMID: 41857306 DOI: 10.1038/s42003-026-09860-z
Abstract

Ulcerative colitis (UC) is a debilitating, immune-mediated inflammatory disorder of the gastrointestinal (GI) tract with far-reaching consequences on distal organs, including the bone marrow. Here, we describe the molecular mechanisms that contribute to UC-induced abnormal hematopoiesis. We show that chronic UC drives HSPC differentiation toward myelopoiesis in an APE1/Ref-1/HIF-1α/IL-1r1-dependent manner. Blockade of the redox-activity of APE1/Ref-1 with APX3330 inhibits the elevated expression of HIF-1α in HSPCs and reverses the aberrant HSPC dynamics under the inflammatory milieu of UC, including suppression of pro-inflammatory Ly6Chi monocytes. Using echinomycin, we pharmacologically blocked HIF-1α activity and found that HIF-1α mediates inflammatory responses via downstream IL-1r1 signaling. Blockade of the redox activity of ref-1 rescues the abnormal HSPC function. Our data highlight the significance of the APE1/Ref-1/HIF-1α/IL-1r1 signaling cascade in aberrant hematopoiesis that contributes to the pathophysiology of chronic UC through a feed-forward loop.

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