infection is closely linked to digestive diseases such as inflammation, ulceration, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. Current treatment relies on antibiotic combinations, but antibiotic resistance increasingly undermines eradication efforts. Urease, a metalloenzyme secreted by , is crucial for bacterial colonization. Traditional urease inhibitors target either the active site or mimic the substrate, but the buried active site poses a challenge for effective inhibition. Moreover, current inhibitors often have non-negligible side effects. Recent research highlights complex interactions during urease maturation, involving auxiliary proteins and nickel ion transfer. These studies suggest that auxiliary proteins involved in metalloenzyme maturation, as well as the process of nickel ion delivery, could be novel targets for inhibitors. This review summarizes nickel ion delivery during urease maturation, interactions between auxiliary proteins, and the structure of the active site. It also categorizes and summarizes half inhibitory concentration (IC) values of existing inhibitors. Finally, we discuss potential inhibitors'mechanisms of action, challenges, and future perspectives, aiming to provide new strategies for eradicating infection.