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

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.