Emerging roles of heme oxygenase 2 (HO-2) in cancer: Implications for diagnosis and therapy.

Heme oxygenases (HOs) are critical enzymes that regulate cellular redox balance, immune signaling, and iron metabolism through the degradation of heme into biliverdin, carbon monoxide (CO), and ferrous iron (Fe). While HO-1, the inducible isoform, has been extensively studied for its roles in tumor progression, inflammation, and therapy resistance, HO-2, the constitutively expressed isoform, has historically received limited attention. However, emerging evidence suggests that HO-2 contributes to cancer pathogenesis through mechanisms distinct from HO-1, including the regulation of tumor-initiating cells, angiogenesis, oxidative stress responses, and immune modulation. These findings position HO-2 as an underexplored yet promising target for cancer diagnosis and therapy. In this review, we summarize the structural and functional differences between HO-1 and HO-2, examine the emerging roles of HO-2 in various malignancies, and discuss its potential as a diagnostic biomarker and therapeutic target. We also highlight recent advances in selective chemical tools that enable the visualization and functional inhibition of HO-2 in cancer models.