Therapeutic potential and mechanisms of flavonoids from Citrus grandis 'Tomentosa' in metabolic dysfunction-associated steatotic liver disease: a focus on immune-inflammatory signaling pathways.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) constitutes a major global health burden, with limited therapeutic options currently available. Flavonoids derived from natural plants exhibit promising antioxidant and anti-inflammatory bioactivities, making them potential preventive and therapeutic agents for metabolic liver diseases. Citrus grandis 'Tomentosa' (CGT) flavonoids have shown hepatoprotective properties in preliminary preclinical investigations. However, a systematic and critical evaluation of the preclinical evidence supporting their application in MASLD, particularly regarding immune-inflammatory regulatory mechanisms, remains absent. This scoping review aimed to comprehensively map and critically appraise preclinical studies concerning the efficacy and molecular mechanisms of CGT flavonoids in MASLD, with a specific focus on immune-inflammatory signaling modulation. Methods: A scoping review methodology was applied to synthesize current preclinical evidence on CGT flavonoids for MASLD. Following standardized literature retrieval and screening procedures, a total of 22 eligible studies were included for qualitative evidence synthesis. The pharmacological effects, mechanistic findings, and methodological limitations of existing studies were systematically summarized and critically assessed. Results: Synthetic analysis of the included studies demonstrated that CGT flavonoids effectively ameliorate hepatic steatosis, inflammatory responses, and oxidative stress in experimental MASLD models. The underlying mechanisms are preliminarily associated with the modulation of NF-κB, MAPK, and JAK-STAT signaling pathways, as well as the regulation of immune cell polarization. Nevertheless, most mechanistic evidence remains indirect and inconclusive, largely derived from non-CGT preparations or non-MASLD models, with a lack of direct target validation. The current body of evidence presents critical research gaps, including potential experimental artifacts caused by pan-assay interference, insufficient pharmacokinetic profiling, and inadequate rigorous studies validating CGT-specific regulatory effects on hepatic immune components, such as Kupffer cells and intrahepatic T-cell subsets under MASLD pathological conditions. Discussion: The present scoping review confirms the preclinical potential of CGT flavonoids as novel botanical candidates for MASLD treatment, primarily through the suppression of hepatic steatosis, oxidative damage, and immune-inflammatory activation. However, existing evidence is methodologically limited and insufficient to support clinical translation. To address current deficiencies and facilitate translational progress, further rigorous mechanistic validation, standardized CGT flavonoid preparation protocols, and well-designed clinical investigations are urgently required. This work provides a balanced, evidence-based, and critical framework to guide future basic research and translational studies targeting CGT flavonoids for MASLD intervention.