Type 2 diabetes mellitus (T2DM) is fundamentally linked to gut microbiota dysbiosis, a condition that triggers a cascade of pathophysiological changes including aberrant host-microbe co-metabolism, compromised intestinal barrier integrity, and chronic low-grade inflammation, which collectively drive insulin resistance. While conventional therapies have limitations, traditional Chinese medicine (TCM) presents a promising therapeutic strategy. This review comprehensively elucidates the pathophysiological link between gut dysbiosis and T2DM. It then systematically summarizes the multi-target mechanisms by which TCM exerts its therapeutic effects, including: remodeling the gut microbial ecosystem; reprogramming host-microbe co-metabolism of short-chain fatty acids (SCFAs), bile acids (BAs), and branched-chain amino acids (BCAAs); reinforcing the intestinal barrier to mitigate metabolic endotoxemia; and modulating key signaling pathways involved in inflammation and immunity, etc. Key clinical evidence is also summarized. Furthermore, the review critically evaluates the preclinical and clinical evidence supporting these mechanisms, highlighting both therapeutic potential and current challenges, such as the need for standardization. Finally, current limitations and future prospects are considered, proposing a path forward for integrating microbiota-targeted TCM therapies into the modern, evidence-based management of T2DM.

Postmenopausal women, elderly individuals, and transfusion-dependent patients are prone to bone marrow iron overload, which is closely associated with iron overload-associated osteoporosis (IOOP). Currently, the treatment of IOOP mainly focuses on promoting iron efflux and alleviating iron-induced damage, but the intervention value of natural active ingredients remains unclear. Naringenin (NAR), as a natural flavonoid, can regulate bone metabolism, yet its role and mechanism in IOOP have not been elucidated. In this study, an in vitro model was established by inducing MC3T3-E1 cells with ferric ammonium citrate (FAC), and an in vivo IOOP model was constructed by inducing mice with iron dextran to investigate the effects and mechanisms of NAR. The results showed that NAR improved the alkaline phosphatase (ALP) activity and mineralization capacity of FAC-induced iron-overloaded cells, upregulated the expression of collagen I (Col1a1) and runt-related transcription factor 2 (Runx2), reduced the accumulation of reactive oxygen species (ROS) and lipid peroxide (LPO), attenuated mitochondrial membrane potential (MMP) impairment, and inhibited apoptosis. In in vivo experiments, NAR restored the density and quantity of trabecular bone in iron-overloaded mice. Mechanistically, RNA sequencing indicated that the effect of NAR was associated with transcription factor EB (Tfeb)-dependent transcription: NAR promoted Tfeb nuclear translocation and upregulated p62 transcription under iron overload conditions. Co-immunoprecipitation (Co-IP) demonstrated that NAR enhanced the binding of p62 to kelch-like ECH associated protein 1 (Keap1), while increasing Nrf2 phosphorylation and upregulating its key effector proteins HO-1 and NQO1. Functional validation showed that the Nrf2 antagonist ML385 or siRNA could block the effects of NAR without affecting Tfeb expression, whereas the Tfeb inhibitor eltrombopag simultaneously inhibited Nrf2 expression and NAR-induced effects. In conclusion, NAR alleviates iron overload-induced oxidative damage and osteogenic disorders via the Tfeb/p62/Nrf2 pathway, suggesting that it may serve as a potential therapeutic agent for IOOP.

Ulcerative colitis (UC) is defined as a chronic inflammatory disease with recurrent episodes, and current therapeutic strategies for this gastrointestinal disorder often fail to achieve satisfactory clinical outcomes. This clinical challenge underscores an urgent requirement to develop alternative treatment strategies. Patchouli alcohol (PA), a natural compound exhibiting anti-inflammatory and antioxidant properties, has shown potential; however, its precise mechanisms of action in UC remain to be fully elucidated. Our study shows that PA can effectively alleviate the symptoms of dextran sulfate sodium (DSS)-induced UC in mice. This therapeutic effect is achieved by reducing intestinal barrier impairment and inhibiting inflammatory reactions. In an LPS-induced inflammatory model using RAW264.7 cells, PA significantly downregulated the mRNA expression of il-1β and il-6. Mechanistically, protein disulfide isomerase (PDI) was identified as a direct target of PA. By inhibiting IRE1 activation via PDI, PA mitigates endoplasmic reticulum stress, thereby reducing intestinal epithelial injury and ultimately alleviating the severity of UC. In this research, it is determined that the ability of PA to protect the intestinal epithelial barrier is brought about by its specific targeting of PDI, which alleviates consequent endoplasmic reticulum stress and prevents cellular damage.

Hypertension raises cardiovascular risk via vascular remodeling, worsened by oxidative stress-linked VSMC dysfunction. Genistein (Gen), an antioxidant isoflavone, protects against cardiovascular diseases, but its role in hypertensive remodeling is unclear. This study explores if Gen eases remodeling by inhibiting oxidative stress via the GSK3β/FYN/Nrf2 pathway. In vivo, spontaneously hypertensive rats (SHR) and normotensive WKY rats got Gen (10−20 mg·kg⁻¹·d⁻¹) or valsartan (Val) for 10 weeks; aortic tissues were tested for morphology (HE/Masson), proliferation (PCNA), migration (MMP2/9), oxidative stress (NOX4), and VSMC phenotype (α-SMA/OPN). In vitro, SHR/WKY VSMCs were treated with Gen (10−40 μmol·L⁻¹) to check proliferation (EdU), migration (scratch/Transwell), ROS, and Nrf2 markers. Network pharmacology predicts Gen inhibits vascular remodeling via reducing hypertension-related oxidative stress, verified by EdU, scratch, Transwell, and Western blot. Gen reduced SHR blood pressure, vascular wall thickness, and fibrosis, reversing PCNA, MMP2/9, NOX4, OPN overexpression and α-SMA underexpression. In VSMCs, it dose-dependently inhibited proliferation/migration, reduced ROS, and restored Nrf2 pathway activity. Network analysis found 52 shared targets, with GSK3β, FYN, Nrf2 as key nodes. Gen and pGSK3β inhibitor SNP reversed GSK3β/FYN overexpression and Nrf2 underexpression; Nrf2 inhibitor ML385 barely affected pGSK3β/FYN. Thus, Nrf2 may lie downstream of GSK3β and FYN. Gen inhibits oxidative stress injury in the aortic tissue of SHR rats through the GSK3β/FYN/Nrf2 pathway, thereby reducing vascular remodeling in hypertension, lowering blood pressure, and exerting a protective effect on vascular lesions in hypertension. These findings provide new experimental evidence for Gen as a potential therapeutic agent against hypertensive vascular remodeling.

Self-assembled nanoaggregates (SANs) derived from herbal decoctions have emerged as promising natural nanomedicines. However, their formation patterns in multi-herb formulations and therapeutic roles in central nervous system disorders remain unclear. Wuzhuyu decoction (WZYD) is a classical formula for migraine treatment. Here, we reveal that SANs in WZYD (N-WZYDs) are formed through synergistic interactions among multiple herbal ingredients with Euodiae Fructus as the focus. N-WZYDs consisted mainly of proteoglycan scaffolds and small-molecule active components. In chronic migraine (CM) rat models, N-WZYDs significantly alleviated symptoms with efficacy comparable to that of WZYD, potentially via inhibition of the IL-33/ST2/TRPA1 signaling pathway. In Caco-2 cells, transport studies indicated that ginsenoside Rg₁, dehydroevodiamine, and rutaevin were poorly absorbed, whereas evodiamine and 6-gingerol were moderately absorbed but significantly active in efflux, indicating the intestine as a key site of action. As an oral medication, intact N-WZYDs accumulated primarily in the intestines and could be internalized by Caco-2 and enterochromaffin cells. Crucially, N-WZYDs promoted serotonin release from enterochromaffin cells more effectively than free active molecules alone and increased peripheral serotonin levels, thereby alleviating CM. By investigating the formation patterns, anti-CM mechanisms, and absorption behaviors of N-WZYDs, this study elucidated their material basis and brain−intestine interactions in treating CM, supporting their further development as therapeutic agents or drug delivery systems.

Cisplatin (DDP) remains a standard therapy for triple-negative breast cancer (TNBC), yet intrinsic or acquired resistance often limits its efficacy; here, we report that Ramulus Mori alkaloids (SZ-A), an approved botanical α-glucosidase inhibitors, synergize with DDP to suppress TNBC progression in vitro and in vivo by driving PLA2G2A-dependent ceramide accumulation. Combining SZ-A with DDP synergistically inhibits viability, clonogenicity, migration, and invasion, induces S-phase arrest and apoptosis, and attenuates tumor growth in xenograft models. Mechanistically, SZ-A directly binds to and stabilizes PLA2G2A, blocking its autophagic-lysosomal degradation, leading to accumulated PLA2G2A that suppresses fatty acid oxidation and triggers ceramide accrual via ADIPOR2 inhibition. Genetic ablation of PLA2G2A abrogates these effects. DDP further enhances SZ-A-induced PLA2G2A upregulation and ceramide accumulation, resulting amplified cytotoxicity. Our findings reveal SZ-A as a chemosensitizing agent that enhances the efficacy of DDP in TNBC.

Gelsemium elegans (G. elegans) is a toxic medicinal plant traditionally used to treat chronic pain, with its toxicity linked to indole alkaloids such as gelsemine and humantenmine (HMT). Chronic pain often co-occurs with depression, a condition known to disrupt host-microbiota interactions, potentially affecting drug metabolism and toxicity. However, the impact of comorbid depression on the toxicity of G. elegans remains unclear. This study investigates how depression exacerbates the neurotoxicity of G. elegans and explores the role of the gut microbiota−host metabolic axis in this process. Depression-model mice were treated with G. elegans aqueous extract, gelsemine and HMT. Multi-omics approaches, including 16S rRNA sequencing and shotgun metagenomics, were used to analyze microbiota changes under depressive conditions. Functional validation was performed using pseudo-germ-free mice, fecal microbiota transplantation, and supplementation with Clostridium species and lithocholic acid (LCA), as well as pregnane X receptor (Pxr) knockout models. The results showed that depression significantly heightened the neurotoxicity of G. elegans, gelsemine and HMT. Mechanistically, depression reduced Clostridium abundance and LCA levels, impairing PXR activation and downregulating hepatic CYP3A11 expression. This disruption of the Clostridium-LCA-PXR-CYP3A11 axis hindered the detoxification of indole alkaloids, leading to increased systemic exposure and exacerbated neurotoxicity. Restoration of this pathway through Clostridium or LCA supplementation alleviated the toxicity. These findings highlight the role of the Clostridium-LCA-PXR-CYP3A11 axis in the altered toxicity of G. elegans in a depressive state, and suggest that Clostridium species and their metabolites may serve as a potential strategy for mitigating toxicity.

Glycosyltransferases (GTs) are key enzymes in the glycosylation of plant secondary metabolites, primarily catalyzing the transfer of a sugar moiety from an activated donor to a specific acceptor molecule. Triterpenoid saponins, an abundant and diverse group of natural products, are composed of triterpenoid aglycones and one or more sugar chains, under the catalysis of GTs. Phytolacca Radix is a traditional Chinese medicine containing over 40 triterpenoid saponins with pharmacological values. However, the identification of glycosyltransferases related to triterpenoid saponin synthesis from Phytolacca species remains scarce. In this study, a novel glycosyltransferase, PamUGT, was identified from Phytolacca americana. PamUGT exhibits catalytic activity toward 28-/30-COOH of pentacyclic triterpenoids, and it exhibits a preference for the C-30 position when both carboxyl groups are available. To our knowledge, PamUGT is the first glycosyltransferase identified in Phytolacca species that can catalyze triterpenoids. Further analysis of substrate specificity revealed that PamUGT catalyzes the glycosylation of a wide range of compounds, including triterpenoids, flavonoids, diterpenoids, alkaloids, and phenolic acids. Our findings identify a highly promiscuous glycosyltransferase, offering a valuable enzymatic tool for modifying diverse natural products.

Systematical screening of the metabolic profile of marine fungus Aspergillus sp. EGF 15-0-3 using OSMAC-GNPS molecular networking cascade followed by target isolation of the environmental-induced products resulted the identification of eight unprecedented indole diketopiperazine-based hybrids (1−8) featuring three distinct chemical backbones. The structures of the obtained compounds were established by combination of extensive spectroscopic analyses, X-ray crystallography, and ECD calculations. All these environmental-induced metabolites were demonstrated to be unusual tyrosyl-DNA phosphodiesterase 2 inhibitors. Compound 3, as the most outstanding example, showed selective synergistic antitumor effect when combined with the chemotherapeutic drugs.