Omer Habis Alzoubi, Almu’atasim Khamees, Mohammad Basil Alzu’bi, Sarah Feras Freihat, A. Attar, Hanan Abo Sameed, Rawan Alzubi, Amen Ahed Alsamarah, Raghad Yousef Yassin, Khayry Al‐Shami, Bahaa Al-Trad, Raed M. Al-Zoubi, M S Al Zoubi
-associated peptic ulcer disease (PUD). To identify effective urease inhibitors, acetohydroxamic acid (AHA) remains the only FDA-approved agent, with clinical use constrained by toxicity. This review synthesizes current evidence on urease inhibition strategies, encompassing metal-based complexes, organic derivatives, natural products, peptide inhibitors, nanotechnology-enabled systems, and emerging gene-based approaches. Several candidates, including copper-based compounds and the natural alkaloid palmatine (PAL), demonstrate potent urease inhibition and favorable effects in preclinical models. However, translation to clinical practice is limited by safety concerns, instability, and a paucity of human trials. Advancing hybrid molecules, optimized delivery platforms, and combination therapies may enhance therapeutic efficacy. Rigorous clinical evaluation remains essential to establish urease inhibition as a viable strategy in urease-mediated diseases.