HO-1-driven drug resistance in hematological malignancies: Mechanistic insights and advances in targeted therapy.

Authors

Wenbin Lei, Tianzhen Hu, Jishi Wang

Published in

iScience. Volume 29. Issue 3. Pages 114762. Mar 20, 2026. Epub Jan 22, 2026.

Abstract

HO-1 (HMOX1) is a stress-inducible, rate-limiting heme catabolic enzyme aberrantly upregulated across hematologic malignancies and frequently associated with progression, relapse, and poor therapeutic response. This review integrates clinical and experimental evidence and frames HO-1 as a multidimensional resistance hub operating through three interconnected axes. (1) Enzymatic axis: heme degradation products (CO, biliverdin/bilirubin, and Fe²⁺) buffer therapy-induced oxidative stress, modulate apoptosis/autophagy, and tune ferroptosis susceptibility in a context- and dose-dependent manner. (2) Non-enzymatic axis: stress-induced truncation and nuclear translocation of HO-1 rewire transcriptional programs by stabilizing NRF2 and engaging epigenetic regulators, converting transient stress cues into durable resistance states. (3) Microenvironmental axis: HO-1 activity in stromal and immune compartments reshapes cytokine networks and suppresses immune recognition (e.g., HLA-C and CD48), reinforcing immune-evasive niches. We systematically summarize translational strategies at three levels: (1) agents directly targeting the HO-1 protein, (2) therapies targeting upstream regulatory pathways, and (3) approaches targeting downstream effectors and the HO-1-shaped immunosuppressive microenvironment.

PMID:
41816301
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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