Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction, posing a substantial global health challenge. This review systematically summarizes the therapeutic potential of berberine, a natural isoquinoline alkaloid, in the management of T2DM. Berberine’s pharmacological activities are discussed from multiple perspectives, including enhancing insulin sensitivity and regulating glucose metabolism—encompassing glycogen synthesis, gluconeogenesis, and glucose transport. The review also highlights berberine’s anti-inflammatory, antioxidant, and epigenetic enzyme-targeting actions and its involvement in key T2DM-related signaling pathways such as AKT, AMPK, and GLUTs. These findings collectively elucidate the multi-targeted and multi-pathway molecular mechanisms underlying berberine’s efficacy against T2DM. Additionally, the review covers the pharmacological activities and molecular mechanisms of berberine in treating T2DM complications—including diabetic nephropathy, retinopathy, cardiomyopathy, neuropathy, and diabetic foot ulcers—as well as its clinical and preclinical applications and the synergistic benefits of combination therapy with agents such as metformin, ginsenoside Rb1, and probiotics. By systematically reviewing the literature retrieved from PubMed and Web of Science up to 2025, this article provides a comprehensive summary of current research, offering a theoretical foundation for the clinical use of berberine in T2DM therapy.

The human gut microbiota serves as a critical hub for host metabolic and immune regulation. Disruption of its homeostasis is closely associated with diseases such as Inflammatory Bowel Disease (IBD), metabolic syndrome, and colorectal cancer. Modern dietary and environmental factors are known to exacerbate this dysbiosis, highlighting the need for innovative interventions capable of modulating the gut ecosystem. Within this context, this review explores the potential of edible fungi, focusing on culinary mushrooms (e.g., Lentinula edodes) and medicinal fungi such as Ganoderma lucidum and Phellinus linteus, which are widely studied in Asia for their health benefits. While consumed as functional foods for their nutritional properties in some countries, they are used in traditional medicine in others. This review examines the role of their bioactive components (e.g., polysaccharides, terpenoids) in remodeling the gut microbiome, thereby highlighting their application in functional foods and dietary interventions. This review systematically examines the pathological mechanisms underlying gut dysbiosis and elucidates how bioactive fungal components (e.g., β-glucans, ganoderic acids) improve intestinal barrier function and immune homeostasis by modulating the composition of the gut microbiota, enhancing the production of SCFAs (short-chain fatty acids), and inhibiting the colonization of pathogens. Current evidence, primarily from preclinical studies, suggests that bioactive fungal components, such as β-glucans from Ganoderma lucidum and polysaccharides from Trametes versicolor, may impart health benefits against metabolic disorders and neoplasms. These benefits are mediated through the modulation of microbiota-derived metabolites (e.g., SCFAs) and epigenetic remodeling mechanisms (e.g., HDAC (Histone Deacetylase) inhibition), suggesting their potential application in functional foods and nutritional strategies. metabolites (e.g., SCFAs) and epigenetic remodeling mechanisms (e.g., HDAC inhibition). However, critical gaps persist, particularly in translating these preclinical findings to humans. Key challenges include understanding their bioavailability, establishing human-relevant dose-response relationships, and elucidating spatiotemporal dynamics within microbiota-host interaction networks. Addressing these gaps requires integration with multi-omics technologies and well-designed clinical trials. Multi-omics and organoid models should be integrated by future research to advance precision medicine applications of fungal-derived therapies.