| Summary: | ABSTRACT The protein disulfide isomerase (PDI) family comprises 21 members that have oxidase, reductase, isomerase, and foldase activities essential for human health and disease. Protein disulfide isomerase A4 (PDIA4) is the largest member in this family. This family is pivotal in various human diseases. This review explores PDIA4 as a representative PDI member and other PDIs from the perspective of their roles in cancer, diabetes, and thrombotic diseases. The natural compounds that target PDIA4 and/or other PDIs are summarized, and a comprehensive overview of their compound screening/identification, functions, mechanisms of action, and therapeutic applications in the diseases is provided. A literature search of studies published between 1990 and 2024 was conducted using PubMed, Web of Science, Google Scholar, SciFinder, and Dictionary of Natural Products databases online. Keywords alone and in combination, such as “PDI,” “PDIA4,” “natural compound,” “inhibitor,” and “disease,” were used to retrieve related publications, followed by manual assessment and selection. The results highlight the functions, mechanisms, and potential interventions of PDIs, with particular focus on PDIA4, in cancer, diabetes, and thrombotic disorders. Nineteen compounds that modulate the enzymatic activity or expression of PDIA4 and/or PDIs and show promising pharmacological functions, unique mechanisms, and novel therapeutic opportunities in managing cancer, metabolic syndromes, and thrombosis are presented. Collectively, the mechanisms for the natural inhibitors of PDIA4 are via disruption of the interaction between PDIA4 and its substrates, leading to activation of executioner procaspases in cancer, inhibition of β‐cell reactive oxygen species (ROS) generating pathways in diabetes, and increased displacement of antithrombin by histidine‐rich glycoprotein in coagulation.
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