Multifaceted Roles of Chloroquines in Gastrointestinal Disorders and Beyond

ABSTRACT Chloroquine (CQ) and hydroxychloroquine (HCQ), originally developed as antimalarial agents, have demonstrated broad pharmacological activity across diverse diseases. As weak lipophilic bases, both compounds accumulate in acidic organelles such as lysosomes, interfering with their function and disrupting key cellular processes. This review explores the therapeutic applications of CQ and HCQ in gastrointestinal (GI) pathologies and beyond, with a focus on molecular and cellular mechanisms. In inflammatory bowel disease, CQ and HCQ modulate autophagy, suppress proinflammatory cytokines, and alter gut microbiota composition, contributing to barrier protection and immune regulation. In colitis‐associated colorectal cancer, both agents inhibit tumor development, enhance the efficacy of 5‐fluorouracil, and reverse drug resistance through autophagy blockade. CQ additionally potentiates PI3K/mTOR‐targeted therapies and natural product‐based treatments in gastric cancer. Moreover, CQ decreases GI motility, potentially delaying gastric emptying, and both agents modulate other GI disorders, including Cheilitis granulomatosa, Whipple's disease, Sjögren's syndrome, and dysphagia. Furthermore, the lysosomotropic properties of CQ may serve as a therapeutic adjunct to improve the efficacy of conventional antibiotics against Mycobacterium tuberculosis . The pharmacodynamic profiles of CQ and HCQ underscore their potential as modulators of immune, microbial, and intracellular signaling networks. While accumulating evidence supports their repositioning across inflammatory and neoplastic GI diseases, further mechanistic studies and clinical validation are required to refine their therapeutic applications.