Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner

Rosemary C. Callahan; Jillian C. Curry; Geetha Bhagavatula; Alyse W. Staley; Rachel E.M. Schaefer; Faiz Minhajuddin; Liheng Zhou; Rane M. Neuhart; Shaikh M. Atif; David J. Orlicky; Ian M. Cartwright; Mark E. Gerich; Calen A. Steiner; Arianne L. Theiss; Caroline H.T. Hall; Sean P. Colgan; Joseph C. Onyiah

doi:10.1172/jci.insight.181032

Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner

Rosemary C. Callahan,¹ Jillian C. Curry,¹ Geetha Bhagavatula,² Alyse W. Staley,³ Rachel E.M. Schaefer,¹ Faiz Minhajuddin,¹ Liheng Zhou,¹ Rane M. Neuhart,² Shaikh M. Atif,⁴ David J. Orlicky,⁵ Ian M. Cartwright,¹ Mark E. Gerich,¹ Calen A. Steiner,¹ Arianne L. Theiss,¹ Caroline H.T. Hall,² Sean P. Colgan,¹ and Joseph C. Onyiah¹

Published December 18, 2025 - More info

View PDF

Abstract

Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 is induced during colitis and tumorigenesis. We also found that HO-1 is upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids, and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and non-oxidative toxicity from heme. In vivo, epithelial HO-1 deficient mice developed significantly fewer and smaller tumors compared to littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from knockout mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: protective against acute heme toxicity, but promoting iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.

Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner

Article tools

Metrics

Go to

Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner

Article tools

Metrics

Go to

Sign up for email alerts