Renaissance of Phoenix Drug Thalidomide—New Insights into Practical Clinical Application and Optimization Strategies for Managing Adverse Effects in Digestive Diseases

Thalidomide, once withdrawn due to teratogenicity, has re-emerged as a repurposed agent to treat a broad spectrum of diseases because of its anti-inflammatory, immunomodulatory, and anti-angiogenic properties. Over the past two decades, thalidomide has also been increasingly used in digestive diseases, including gastrointestinal and hepatobiliary–pancreatic disorders. Despite these expanding indications, its broader clinical use remains restricted by safety concerns and the absence of standardized, evidence-based guidance. In particular, practical strategies for optimizing efficacy while minimizing toxicity have not been systematically summarized. This review aims to provide an updated, integrated, and clinically oriented overview of thalidomide in digestive diseases, summarizing the expanded applications from immune-mediated to non-immune-related conditions, highlighting real-world applications, therapeutic strategies, and approaches to risk mitigation. Furthermore, we discuss structural analogs and novel delivery systems that may enhance safety and efficacy, paving the way for thalidomide’s rational and safe use as a modern “phoenix drug”.