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The metabolism of tryptophan plays a critical role in maintaining immune homeostasis and tolerance, as well as in preventing excessive inflammatory responses. Tryptophan-2,3-dioxygenase (TDO2) is a tetrameric heme protein and serves as one of the pivotal rate-limiting enzymes in the first step of tryptophan metabolism. Dysregulation of TDO2 expression has been observed in various digestive system diseases, encompassing those related to the oral cavity, esophagus, liver, stomach, pancreas, and colon and rectum. Digestive system diseases are the most common clinical diseases, with complex clinical manifestations and interrelated symptoms, and have become a research hotspot in the field of medicine. Studies have demonstrated that aberrant TDO2 expression is closely associated with various clinical manifestations and disease outcomes in patients with digestive system disorders. Consequently, TDO2 has garnered increasing recognition as a promising therapeutic target for digestive system diseases in recent years, attracting growing attention. This article provides a brief overview of the role of TDO2 in the tryptophan pathway, emphasizing its significant involvement in diseases of the digestive system. Strategies targeting TDO2 through specific inhibitors suggest considerable promise in enhancing therapeutic outcomes for digestive diseases. Thus, this review concludes by discussing recent advancements in the development of TDO2 inhibitors. We believe that targeted inhibition of TDO2 combined with immunotherapy, the screening of a large number of natural products, and the assistance of artificial intelligence in drug design will be important directions for developing more effective TDO2 inhibitors and improving treatment outcomes in the future.<\/jats:p>","DOI":"10.3390\/biology14030295","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:49:57Z","timestamp":1742197797000},"page":"295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tryptophan-2,3-Dioxygenase as a Therapeutic Target in Digestive System Diseases"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1256-7894","authenticated-orcid":false,"given":"Zhengsen","family":"Wang","sequence":"first","affiliation":[{"name":"The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianxian","family":"Xie","sequence":"additional","affiliation":[{"name":"The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xue","sequence":"additional","affiliation":[{"name":"The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3572-1006","authenticated-orcid":false,"given":"Yixuan","family":"Chen","sequence":"additional","affiliation":[{"name":"The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/den.13354","article-title":"Applications of artificial intelligence to endoscopy practice: The view from Japan Digestive Disease Week 2018","volume":"31","author":"Togashi","year":"2019","journal-title":"Dig. 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