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

TL;DR

Colonic epithelial HO-1 promotes tumorigenesis by regulating iron and oxidative stress in a context-dependent way.

Contribution

Identifies epithelial HO-1 as a context-dependent regulator of tumorigenesis through iron and ferroptosis.

Findings

HO-1 deficiency in mice reduces tumor number and size in colitis-associated tumorigenesis.

HO-1 deletion decreases iron levels, lipid peroxidation, and proliferation in tumors.

Single-cell RNA sequencing shows HO-1 loss shifts epithelial cells to a stress-adaptive state.

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 was induced during colitis and tumorigenesis. We also found that HO-1 was 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 nonoxidative toxicity from heme. In vivo, epithelial HO-1–deficient mice developed significantly fewer and smaller tumors compared with littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from KO 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: it is protective against acute heme toxicity but promotes iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.

Colonic tumorigenesis in mice is influenced by epithelial heme oxygenase-1, which regulates the balance between epithelial heme metabolism and ferroptosis.

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