From gluten to therapeutics: molecular mechanisms of celiac disease and emerging alternatives to the gluten-free diet

Celiac disease (CD) is a chronic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals. Increasing knowledge regarding gluten-derived peptides, intestinal barrier dysfunction, innate and adaptive immune responses, and host–microbiota interactions has substantially improved our understanding of disease pathogenesis and stimulated the development of novel therapeutic strategies. The present review aims to provide an integrated overview of the biochemical, immunological, clinical, and therapeutic aspects of CD by linking its molecular mechanisms to the rationale underlying emerging treatment approaches. Particular attention is devoted to the roles of toxic and immunogenic gluten peptides, tissue transglutaminase, intestinal permeability, and immune activation as potential therapeutic targets. Although the gluten-free diet remains the only established treatment, long-term adherence is often challenging and may negatively affect the nutritional status and quality of life while posing an economic burden. Consequently, several alternative or adjunctive approaches have been investigated, including gluten-degrading enzymes, transglutaminase 2 inhibitors, immune-targeted therapies, microbiota modulation, genetically modified cereals, and other experimental interventions. Current evidence suggests that several of these strategies show promising preclinical or early clinical results; however, most of these approaches are limited by insufficient efficacy data, small clinical studies, regulatory challenges, or lack of long-term safety information. At present, none of these approaches can replace the gluten-free diet in routine clinical practice. Overall, the future management of CD will likely require personalized and potentially combined therapeutic approaches. Further translational and clinical studies are needed to identify safe, effective, and accessible alternatives capable of complementing or reducing the burden of lifelong dietary treatment.