From mechanism to clinic: a panoramic perspective on targeting HMOX1 to overcome drug resistance

Drug resistance is a pivotal factor leading to the failure of cancer therapy, within which heme oxygenase-1 (HMOX1) plays a complex and paradoxical dual role. On one hand, HMOX1 protects cancer cells from oxidative damage induced by chemotherapeutic drugs through its antioxidant properties. Concurrently, its catalytic downstream product, carbon monoxide (CO), inhibits cancer cell apoptosis, thereby mediating acquired drug resistance. On the other hand, HMOX1 is a key source of intracellular free iron. When its activity is excessively induced, it leads to the accumulation of excessive free iron, triggering the buildup of lipid peroxides and ferroptosis, which presents a novel opportunity to overcome drug resistance. This demonstrates that the function of HMOX1 can switch depending on its degree of activation. Therefore, a thorough analysis of its regulatory network and the mechanisms of its functional switch within different microenvironments is crucial for developing novel therapeutic strategies that target HMOX1 to overcome drug resistance. This review systematically summarizes the multiple mechanisms of HMOX1 in drug resistance, with a focus on HMOX1 inducers and inhibitors, as well as synergistic sensitization strategies in combination with other therapies. It aims to provide a comprehensive theoretical foundation and a forward-looking perspective for translating HMOX1-targeted therapy from basic research to clinical practice.