Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut–liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota–bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein–coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and ⁷⁵Selenium HomotauroCholic acid test (⁷⁵SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.

Although nanomedicine has enabled significant advances in drug delivery, the clinical translation of conventional synthetic nanocarriers is limited by immune clearance, non-specific biodistribution, and gastrointestinal instability. This poses major challenges for therapy targeting the intestines. Cell membrane-coated nanotechnology (CMCT) and membrane vesicle-based systems have emerged as biomimetic platforms integrating synthetic nanomaterials with naturally derived biological interfaces. These biohybrid systems inherit biological functions originating from cells, including immune evasion, prolonged circulation, lesion homing, and microenvironment-responsive interactions, through the direct transfer of intact membrane components. This review summarizes recent advances in CMCT and membrane vesicle-based strategies for intestinal drug delivery. It covers fabrication methodologies, programmable manufacturing approaches, and functional regulation enabled by diverse membrane sources and hybrid engineering designs. Applications in inflammatory bowel disease, colorectal cancer, and intestinal infections are highlighted, emphasizing key therapeutic mechanisms, such as targeting inflammation, neutralizing toxins, modulating the immune system, and regulating the microbiome. We also discuss the major challenges of translation, such as preserving membrane and coating integrity, ensuring oral stability, achieving batch reproducibility, and ensuring biosafety. Overall, this review establishes a conceptual and engineering framework to guide the transition of membrane-based nanocarriers from passive biomimicry to adaptive, clinically translatable intestinal delivery systems.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the results of traditional immunosuppressive therapy are disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients would eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and there is increasing evidence that gut microbiota and bile acids play an important role in cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Understanding the gut microbiota-bile acid network and corresponding immune functions in PBC provides a new perspective for its treatment strategies. Therefore, we summarize the latest advancements in research of gut microbiota and bile acids in PBC and, for the first time, explore the potential of immune factors related to them as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

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”.

Introduction: Lenalidomide is an immunomodulatory drug. Its repurposing for refractory Behcet’s Disease is a promising strategy. Behcet’s Disease is a rare and complex autoinflammatory condition. Current treatment options are limited. This study explored the drug’s therapeutic potential using clinical and computational analyses. Methods: This study included a systematic review of clinical case reports. Computational methods included toxicological predictions, network pharmacology to screen common targets of lenalidomide and Behcet’s Disease, and the construction of protein-protein interaction networks utilizing tools such as ProTox-3.0, ADMETlab 3.0, and Cytoscape. Additionally, molecular docking (AutoDock Vina) and molecular dynamics simulations (GROMACS) were used to assess binding and stability. Results: Clinical data showed low-dose lenalidomide provided rapid symptom relief and appeared to be well tolerated. Computational toxicology revealed a complex, dose-dependent safety profile. Network analysis identified 63 common targets. Seven core genes were found, including IL6, TNF, and JAK1. These genes were enriched in immune pathways, particularly the JAK-STAT cascade. Molecular docking and dynamics confirmed stable binding to key targets like IL6 and JAK1. Discussion: Lenalidomide appears potentially effective in Behcet’s Disease. Its action likely involves multi-target regulation of core immune pathways. Multi-target regulation of the JAKSTAT and TNF signaling cascades directly addresses the core autoinflammatory pathology of Behcet's Disease. The concordance between clinical efficacy and computational findings highlights its repurposing potential. The findings also stress the importance of dose optimization for safety, generating a promising low-dose safety hypothesis. conclusion: Lenalidomide is a viable repurposed therapeutic candidate for refractory Behçet’s Disease. This old drug new use strategy offers a practical and mechanistically supported treatment avenue for this rare disease, demonstrating the value of computational and clinical integration in rare disease therapy development. Conclusion: Lenalidomide is a viable repurposing candidate warranting further clinical investigation for refractory Behcet’s Disease. This strategy provides a mechanistically supported treatment for this rare disease. Combining network pharmacology and molecular dynamics provides a robust preclinical rationale for repurposing lenalidomide in Behcet's Disease.