Traditional Chinese medicine (TCM) exerts unique therapeutic effects, while some unfavorable physicochemical properties limit its therapeutic potential. Exosomes are involved in cellular communication and may enhance the efficacy of TCM. The relationship between TCM and exosomes is supported by the connection between exosomes and the theory of “Qi, Xue and Ye” (one of the basic theories of TCM). Also, the functional resemblance between exosomes and Qi, which is less researched. We fill this gap by systematically summarizing exosomes from different sources with therapeutic effects and exploring the mechanisms and implications of exosomes in TCM treatment. TCM and exosomes undergo two-way communication, with TCM affecting exosomes and exosomes loading TCM monomers. The dual roles of exosomes as destructive agents in disease development are also emphasized; current obstacles and future scope of TCM–exosome therapeutic strategies are fully discussed. The objective of this review is to stimulate further investigation and create a new application of TCM.

Neuroinflammation is a central pathological process in a wide range of central nervous system disorders, yet therapeutic strategies directed solely at single inflammatory targets have shown limited efficacy. Gut–brain axis dysfunction may contribute to neuroinflammatory progression through interconnected metabolic, immune, neural, and vesicle-associated routes. Icariin, a major flavonoid glycoside from Epimedii Folium, has attracted attention because of its anti-inflammatory, neuroprotective, and microbiota-modulating properties. In this review, we summarize current evidence for the anti-neuroinflammatory effects of icariin and explicitly stratify the evidence into three levels: direct icariin-related findings, icariin-related findings without causal gut–brain validation, and mechanisms inferred from broader gut–brain axis biology. Available studies provide relatively stronger support for intestinal barrier protection, microbiota remodeling, peripheral cytokine suppression, and central inflammatory pathway regulation. In contrast, short-chain fatty acid (SCFA)-associated signaling, vagal neuroimmune communication, and extracellular vesicle (EV)-mediated cargo transfer remain plausible but incompletely validated candidate routes. We further compare icariin with its major microbial metabolites, especially icariside II and icaritin, because oral icariin may act partly through metabolite-mediated exposure rather than through robust brain penetration of the parent compound. Major limitations include insufficient causal perturbation, incomplete organ-specific pharmacokinetic data, inter-individual microbiota variability, and uncertain therapeutic time windows. Overall, icariin emerges as a promising multi-target natural product for anti-neuroinflammatory research, but the causal hierarchy and translational relevance of proposed gut–brain pathways require direct validation.

Breast cancer (BC) has become the most prevalent cancer worldwide, and BC patients have the highest rate of depression of all cancer patients. However, previous studies, especially studies based on clinical sample data, have failed to reveal exactly how depression affects BC. Two-sample Mendelian randomization (TSMR) was used to determine the causal relationship between depression and BC. Transcriptomics and metabolomics were used to analyze BC samples from nondepressed and depressed patients and to validate differentially expressed genes and key metabolites in vitro. Molecular docking techniques were used to identify compounds that regulate key targets and validate the functions of the compounds in in vitro and in vivo animal models. Depression was identified as a risk factor for BC by the TSMR analysis. On the basis of clinical samples, for the first time, we identified PPARγ and norepinephrine (NE) as key genes and metabolites that mediate the pro-BC effects of depression. In addition, we demonstrated that quercetin can target PPARγ and reverse the procancer effects of PPARγ inhibition mediated by chronic stress in BC cells. Moreover, we found that PPARγ may be associated with the inhibition of CD8⁺ T cells in the tumor immune microenvironment. In conclusion, depression can increase the infiltration level of NE in tumors and inhibit the expression of PPARγ in tumor cells, thus promoting the proliferation of BC cells and inhibiting the infiltration of CD8⁺ T cells in the immune microenvironment, ultimately leading to accelerated tumor growth. Quercetin can target PPARγ and reverse this cancer-promoting process.

Artemisia annua L. (A. annua) has long been documented in traditional Chinese medicine for managing hemorrhagic conditions, attributed to its cooling and hemostatic properties. These historical applications suggest a potential role of A. annua in platelet-related disorders, although its hematopoietic mechanisms remain unclear. To investigate the thrombopoietic activity of A. annua, identify its bioactive constituent, and elucidate the molecular mechanisms underlying its effects on thrombopoiesis. Chemical profiling identified major compounds in A. annua. MK differentiation was assessed in K562, Meg-01 cells, and primary murine haematopoietic stem and progenitor cells (HSPCs). A murine radiation-induced thrombocytopenia (RIT) model was used to evaluatein vivo efficacy. Molecular docking, drug affinity responsive target stability (DARTS), and signaling assays were conducted to explore molecular mechanisms. A. annua promoted MK differentiation, upregulating CD41/CD42b and enhancing polyploidization. Artemisinin was identified as the principal active compound. It promoted MK maturation in vitro and restored platelet counts, MK numbers, and HSPC populations in RIT mice without inducing systemic toxicity. Artemisinin also reduced bone marrow (BM) apoptosis and DNA damage while restoring platelet function. Mechanistically, artemisinin directly bound to FLT3 and activated the FLT3/MAPK pathway, leading to increased phosphorylation of MEK/ERK and upregulation of NF-E2 and TAL1. FLT3 and ERK inhibition abrogated these effects. Artemisinin is a potent thrombopoietic agent that acts via direct activation of FLT3 and its downstream MAPK signaling cascade. The findings identify FLT3 as a novel therapeutic target for thrombocytopenia and support the potential clinical application of artemisinin in radiation-related hematological disorders.

Oral squamous cell carcinoma (OSCC) poses a significant global health challenge due to its high recurrence rate and resistance to cisplatin. While DNA repair pathways contribute to chemoresistance, the role of scaffold proteins in stabilizing repair enzymes remains largely unexplored. This study aimed to elucidate the function of CCDC43 in cisplatin sensitivity and to identify a natural product targeting the CCDC43-PNKP axis. Bioinformatic analyses were conducted using bulk and single-cell transcriptomic and proteomic datasets. Molecular assays investigated the CCDC43-PNKP interaction and the impact of neferine on this axis. Xenograft models assessed the efficacy of combined neferine and cisplatin treatment. Machine learning identified CCDC43 as a key prognostic marker and driver of cisplatin resistance. CCDC43 was upregulated in OSCC epithelial cells and associated with poor survival. CCDC43 bound and stabilized PNKP by inhibiting ubiquitin-dependent degradation, thereby enhancing DNA repair and reducing cisplatin sensitivity. Through artificial intelligence-based virtual screening and experimental validation, neferine was found to disrupt the CCDC43-PNKP interaction, promoted PNKP degradation, increased cisplatin-induced DNA damage, and suppressed OSCC growth without acute toxicity. Collectively, the CCDC43-PNKP axis represents a critical therapeutic target in OSCC. Neferine is a promising ethnopharmacological agent capable of improving cisplatin sensitivity by targeting this pathway.

Chronic cerebral hypoperfusion (CCH) is a major contributor to vascular cognitive impairment (VCI), often resulting in progressive learning and memory deficits. Quercetin (Qu), a natural flavonoid with potent anti-inflammatory and antioxidant properties, demonstrates neuroprotective potential against ischemic injury, yet its mechanism of action remains incompletely understood. In this study, a rat model of CCH was established by bilateral common carotid artery occlusion, followed by Qu administration at doses of 20, 40, and 80 mg·kg⁻¹. In parallel, HT22 cells subjected to oxygen-glucose deprivation (OGD) were treated with Qu at 5, 10, or 20 μmol·L⁻¹. Behavioral tests, histological staining, ELISA, and Western blot were used to assess cognitive performance, neuronal injury, lysosomal activity, NF-κB pathway activation, and inflammatory cytokine levels. Hippocampal RNA sequencing was also performed. Our results demonstrate that Qu greatly improved cognitive performance and attenuated neuronal damage in both the cerebral cortex and hippocampus. Mechanistically, Qu improved lysosomal function and suppressed NF-κB-mediated neuroinflammatory response, leading to less production of pro-inflammatory cytokines. Notably, co-administration of a lysosomal inhibitor attenuated the neuroprotective effects of Qu, underscoring the functional importance of lysosomal activation. In conclusion, Qu alleviates CCH-induced cognitive decline and neurodegeneration by restoring lysosomal function and inhibiting NF-κB-driven neuroinflammation. These findings support the therapeutic potential of Qu for VCI and provide a rationale for its further development as a neuroprotective agent.

Hepatic fibrosis is a pathological response to persistent liver injury, characterized by activation of hepatic stellate cells (HSCs) and excessive extracellular matrix (ECM) deposition. Isoimperatorin (ISOIM), a coumarin derivative isolated from Angelica dahurica, has been reported to possess analgesic and anti-inflammatory properties. This study investigated the hepatoprotective potential of ISOIM and its underlying mechanisms against hepatic fibrosis. C57BL/6J mice were intraperitoneally injected with thioacetamide (TAA, 100−200 mg·kg⁻¹) for 5 weeks and received ISOIM (5 or 8 mg·kg⁻¹) administration. HSCs and LX-2 were stimulated with transforming growth factor-β (TGF-β, 10 nmol·L⁻¹) or conditioned medium from lipopolysaccharide (LPS)-primed THP-1 (LPS-MØ-CM), followed by ISOIM (0.78, 1.56, 3.125 μmol·L⁻¹) treatment. In TAA-induced mice, ISOIM reduced serum transaminases, attenuated ECM deposition and histopathological damage, alleviated inflammatory responses, and decreased hepatocyte apoptosis. In activated HSCs, ISOIM inhibited ECM accumulation, reduced inflammatory cytokine expression and promoted apoptotic signaling. Mechanistically, ISOIM showed a potential interaction with LXRα/β, reduced HMGB1-associated inflammatory signaling, and suppressed activation of the HMGB1/NLRP3 signaling, accompanied by enhanced caspase-3-mediated apoptotic signaling in activated HSCs. These effects were consistent with those of the LXRα/β agonist GW3965 and were markedly attenuated by LXRβ or LXRα silencing. In addition, ISOIM regulated LXRα/β and the HMGB1-NLRP3 axis, reduced α-SMA expression, and promoted apoptotic signaling in LX-2 cultured with LPS-MØ-CM. Collectively, ISOIM exerted hepatoprotective effects by activating LXRα/β, inhibiting HMGB1/NLRP3 signaling, and promoting apoptosis of activated HSCs within the hepatic microenvironment.

Breast cancer (BC) remains a significant challenge to women’s health, and identifying effective molecular targets is crucial for therapeutic advancement. Krüppel-like factor 5 (KLF5), an oncogenic transcription factor, is highly expressed in BC, yet its development as a therapeutic target has been hindered by its intrinsically disordered structure. In this study, we identified Brevilin A (BrA), a natural sesquiterpenoid fromCentipeda minima, as a potent KLF5 degrader. We demonstrated that BrA directly binds to KLF5 and promotes its ubiquitin-mediated degradation through the E3 ligase WWP2. BrA significantly inhibited BC cell proliferation and induced severe mitochondrial dysfunction and endoplasmic reticulum (ER) stress, as evidenced by reduced mitochondrial respiration and activation of the PERK-EIF2α pathway. Mechanistically, BrA enhanced the recruitment of WWP2 to KLF5, leading to its polyubiquitination and subsequent proteasomal degradation. KLF5 overexpression effectively rescued the mitochondrial and ER homeostasis disrupted by BrA, whereas KLF5 knockdown rendered cells insensitive to BrA-induced cytotoxicity. In vivo studies using zebrafish and nude mouse xenograft models confirmed that BrA suppressed tumor growth by downregulating KLF5 and its downstream metabolic effectors. Collectively, our findings reveal that BrA exerts antitumor effects by promoting WWP2-mediated ubiquitination and degradation of KLF5, thereby disrupting mitochondrial and ER integrity, highlighting its potential as a natural lead compound for BC treatment.

Alzheimer’s disease (AD) is a severe neurodegenerative disorder, with persistent neuroinflammation and impaired autophagy recognized as key contributing factors. CCA is a naturally occurring cassane diterpene compound derived from the seed of Caesalpinia bonduc. Our research is the first to explore the role and mechanism of CCA in treating Alzheimer’s disease. We assessed the levels of pro-inflammatory cytokines and autophagy in BV2 cells following lipopolysaccharide (LPS) treatment and anti-neuroinflammatory effects of CCA were evaluated in LPS-induced mice, with the underlying mechanisms explored using transcriptomic. Additionally, we examined the cognitive-enhancing effects of CCA in APP/PS1 mice and investigatedCaesalpinia bonduc associated molecular mechanisms through proteomic analysis, immunohistochemistry (IHC) and immunofluorescence (IF) assays. Finally, the molecular target of CCA was validated using molecular dynamics simulations and cellular thermal shift assay (CETSA). CCA can down-regulate the mRNA levels of inflammatory factors in BV2 cells stimulated by LPS, and has good permeability of blood-brain barrier. Furthermore, CCA ameliorated cognitive impairment and neuronal damage in both LPS-induced and APP/PS1 mice. And demonstrated that CCA mitigates neuroinflammation by driving microglial polarization from M1 to M2, a process potentially mediated by the AMPK/NF-κB pathway, thereby reducing tau pathology. Proteomic profiling and IHC revealed that CCA upregulates FOXG1 expression in APP/PS1 mice. Furthermore, the scTenifoldKnk confirmed that AMPK has a significant impact on the regulation of autophagy and inflammation response. Our findings verified that CCA exhibits anti-neuroinflammatory activity by AMPK/NF-κB pathway and activates autophagy via the AMPK-mTOR-FOXG1 signaling axis, which underscores its potential as a novel therapeutic option for the treatment of AD.