Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), yet effective therapeutic options remain limited. Although notoginsenoside R1 (NGR1) is a major bioactive saponin isolated from Panax notoginseng with established anti-inflammatory and anti-oxidant properties, its hepatoprotective potential and underlying mechanisms in APAP-induced liver injury (AILI) have not been systematically investigated. In this study, we established an AILI mouse model and evaluated the protective effects of NGR1 through biochemical assays, histopathology, Western blotting, and immunofluorescence, complemented by integrative transcriptomic, metabolomic, and gut microbiota analyses. Mechanistic involvement of the MAPK/mTOR-autophagy pathway was further validated using L-leucine as a pharmacological activator of mTOR. NGR1 markedly attenuated AILI, as reflected by reduced serum ALT/AST levels, improved hepatic histology, and increased survival in acute liver failure. NGR1 suppressed inflammatory responses by decreasing IL-1[Formula: see text], IL-6, and TNF-[Formula: see text] levels and alleviated oxidative stress by restoring GSH and SOD while reducing MPO, ROS, and MDA accumulation. Multi-omics analysis revealed significant enrichment of MAPK/mTOR signaling, autophagy, ferroptosis, and glutathione metabolism pathways. Mechanistically, NGR1 promoted autophagic flux (increased LC3-II/I, ATG5, and ATG7 with decreased p62), inhibited ferroptosis (upregulation of GPX4 and SLC7A11 with downregulation of ACSL4), and suppressed APAP-induced activation of the MAPK/mTOR pathway. Pharmacological activation of mTOR by L-leucine partly abolished the protective effects of NGR1, reversing autophagy activation and restoring inflammatory and oxidative injury. These findings collectively demonstrate that NGR1 protects against AILI by inhibiting MAPK/mTOR signaling, restoring autophagy, and suppressing ferroptosis, highlighting NGR1 as a promising therapeutic candidate for APAP-induced hepatotoxicity.

The rhubarb root and the senna leaf are two commonly used laxative herbs for functional constipation, containing dianthrones and free anthraquinones. As a free anthraquinone, emodin is a crucial constituent isolated from laxative botanicals, and it is particularly abundant in the rhubarb root, a key ingredient in the classic Chinese medicine formula MaZiRenWan (or herbal medicine CDD-2101). This study explored emodin's anti-malignancy, anti-inflammation, and underlying mechanisms. We examined emodin and other anthraquinones on human colorectal cancer cell proliferation, then used Apc[Min/][Formula: see text] mice to assess effects on animal lifespan, intestinal tumor multiplicity, inflammatory cytokines, and adaptive immunity. Results showed MaZiRenWan extract inhibited HCT-116/HT-29 human cancer cells. However, two primary dianthrone sennosides, sennoside A and sennoside B, did not demonstrate such pronounced effects. Three free anthraquinones, emodin, aloe-emodin, and rhein, displayed antiproliferative effects on cancer cells, which were observed to be significantly concentration- and time-dependent, with emodin demonstrating the strongest action. Emodin was found to induce cell cycle arrest during the S-G2/M phases and trigger apoptosis. In vivo, emodin extended Apc[Min/[Formula: see text]] mice lifespan, reduced gut tumors, downregulated gut tissue levels of key pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-17A, IL-8, G-CSF, and GM-CSF; this result was supported by the IL-8 secretion test. Emodin had no inhibitory effect on regulatory Treg cell differentiation, yet it effectively suppressed the Th1 and the Th17 cell differentiation. In conclusion, emodin prevents colorectal cancer via inhibiting cell growth, anti-inflammation, and adaptive immunity modulation, highlighting its potential in inflammation-associated colorectal cancer prevention.

Ginsenoside Rg3, a rare protopanaxadiol-type saponin enriched during the heat processing of Panax ginseng, has attracted increasing attention as a multitarget anticancer agent. This systematic review examines the anticancer potential of Rg3 through comprehensive searches of the PubMed and Web of Science databases, with a focus on peer-reviewed preclinical and clinical studies. The therapeutic efficacy of Rg3 is critically influenced by its stereochemical configuration, concentration-dependent bidirectional regulation, and pharmacokinetic constraints, including poor oral bioavailability, rapid clearance, and gut microbiota-mediated metabolism. Nanocarrier-based and targeted delivery systems have substantially improved its pharmacokinetic profile and tumor accumulation, supporting its further development for anticancer applications. Within this pharmacological context, Rg3 exhibits broad-spectrum anticancer activity across multiple solid tumors, including hepatocellular carcinoma, melanoma, lung, ovarian, breast, colon, gastric, and prostate cancers, as well as osteosarcoma, renal cancer, lung adenocarcinoma, glioblastoma, gallbladder, nasopharyngeal, cervical, and pancreatic cancers, and the hematological malignancy multiple myeloma. Mechanistically, Rg3 suppresses cancer progression through coordinated regulation of proliferation, apoptosis, autophagy, ferroptosis, angiogenesis, epithelial-mesenchymal transition, cancer stemness, immune evasion, and redox homeostasis, primarily involving the PI3K/AKT/mTOR, NF-[Formula: see text]B, MAPK, Wnt/[Formula: see text]-catenin, EGFR, and p53 pathways. These effects reflect transferable network-level mechanisms rather than tumor type-restricted actions. Moreover, Rg3 demonstrates synergistic effects with chemotherapy, radiotherapy, targeted therapy, and immunotherapy, while reversing drug resistance and attenuating treatment-related toxicity in multiple cancer models and clinical settings. Overall, this review systematically integrates current evidence on the pharmacokinetics, anticancer spectrum, molecular mechanisms, synergistic combinations, immunomodulatory effects, and clinical applications of Rg3, providing a concise framework for the rational development of Rg3-based combination strategies in precision cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of malignancies. Quercetin (QCT), a natural flavonoid, exhibits broad pharmacological activities and minimal toxicity, which makes it a promising candidate for cancer therapy. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic target for cancer treatment. Emerging evidence highlights ferroptosis as a key tumor-suppressive mechanism because it directly kills tumor cells independently of apoptotic effectors and necrosis inducers. The focus of this work is to investigate the significance of QCT in inhibiting PDAC via ferroptosis induction. The antitumor effects of QCT on PDAC were investigated both in vitro, through analyses of cell proliferation and apoptosis, and in vivo by using tumor xenograft models. The in vitro validation results confirmed that QCT inhibited PDAC cell proliferation by modulating ferroptosis via the elevation of intracellular Fe[Formula: see text] and lipid peroxidation. In addition, QCT promoted autophagy by upregulating expression of LC3 and ATG5 autophagy-related proteins. Mechanistically, QCT sensitized PDAC cells to ferroptosis by facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe[Formula: see text] content. Conversely, silencing NCOA4 further supported our mechanistic studies by restoring the downregulated mitochondrial respiration and glycolytic capacity. This study likewise served to demonstrate the significance of NCOA4-mediated ferritinophagy in promoting QCT-regulated tumor cell death. Taken together, our findings reveal the direct protein targets and molecular mechanisms through which QCT enhances antitumor activity, and thus suggest that the targeted induction of ferroptosis via QCT administration may represent a valuable and effective strategy for treating PDAC.

Frequently evolving into a highly immunosuppressive niche that facilitates tumor growth and metastasis, the tumor microenvironment (TME) serves as the primary site for interactions between tumor cells and the host immune system. Reversing this immunosuppressive state therefore represents a pivotal strategy for antitumor therapy. Natural products possess the distinct advantages of multi-targeted and multi-pathway mechanisms, as well as the capacity to enhance therapeutic efficacy while attenuating systemic toxicity. These characteristics perfectly align with the core principles of antitumor immunotherapy. Accumulating evidence demonstrates that natural products including Ganoderma lucidum polysaccharides, Astragalus polysaccharides, and Lycium barbarum polysaccharides, as well as bioactive single compounds such as curcumin, resveratrol, and bufalin, exert potent antitumor immunotherapeutic effects by remodeling the suppressive TME. Consequently, they are increasingly being utilized as synergists or adjuvants in advanced therapeutic modalities, which include adoptive immune cell therapy, cancer vaccines, and immune checkpoint inhibitors. In addition, the discovery of novel potential regulatory factors for tumor immunotherapy from natural products has attracted significant attention. This review provides a comprehensive overview of the latest progress on how natural products reshape the immunosuppressive landscape and enhance the systemic antitumor response. Ultimately, this review both underscores the immense translational potential of natural products in tumor immunotherapy and highlights critical directions for future standardized research.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by immune dysregulation, intestinal microbiota imbalance, and disruption of the mucosal barrier. Current clinical management is challenged by high relapse rates and significant interindividual variability in drug responses. Traditional Chinese Medicine (TCM) has shown unique therapeutic advantages in UC treatment through multi-targeted interventions such as the modulation of the immune-microbiota axis, restoration of mucosal integrity, and reduction of oxidative stress. However, two major bottlenecks, the complex pharmacokinetic (PK) behaviors of multi-component systems and the lack of personalized dosing strategies, hinder the optimization of its clinical efficacy. This review emphasizes the PK underpinnings of TCM therapy for UC by integrating current knowledge on absorption, distribution, metabolism, and excretion (ADME) characteristics, both PK and pharmacodynamic (PD) and analytical modeling advances, and PK-informed strategies that facilitate individualized clinical use. By integrating PK profiling with patient-specific variables, this review aims both to provide a theoretical and methodological framework for precision TCM in UC management and to ultimately facilitate a paradigm shift from empirical therapy to quantitatively optimized interventions.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and lacks effective therapies. Luteolin, a dietary flavonoid with broad antitumor activity, has shown anti-PDAC potential, yet whether it acts through RAS/ERK/DRP1-dependent mitochondrial fission and pyroptosis remains unclear. Human PDAC cells were treated with luteolin to evaluate its effects on malignant phenotypes, including proliferation, apoptosis, migration, and invasion. Mitochondrial function and morphology were assessed by measuring mitochondrial membrane potential, mitochondrial ROS production, and mitochondrial network remodeling. Pyroptosis was evaluated by measuring NLRP3 inflammasome activation, pyroptosis-related proteins, and cell injury-associated indicators. Mechanistically, MCC950, RAS overexpression, DRP1 overexpression, EGF stimulation, and Mdivi-1 treatment were used to determine the involvement of NLRP3 inflammasome activation and the RAS/ERK/DRP1-mediated mitochondrial fission pathway. A subcutaneous xenograft model was further established to validate the antitumor effect of luteolin in vivo. Luteolin significantly inhibited the growth, migration, and invasion of PANC-1 and MIA PaCa-2 cells, while increasing apoptosis. It induced mitochondrial membrane potential loss, enhanced mitochondrial ROS production, reduced mitochondrial number, suppressed mitochondrial fission, and promoted mitochondrial network remodeling. Luteolin also upregulated NLRP3 inflammasome- and pyroptosis-related proteins, and these effects were partially reversed by MCC950. Mechanistically, luteolin inhibited the RAS/ERK/DRP1 pathway, whereas RAS or DRP1 overexpression partially attenuated luteolin-induced mitochondrial dysfunction and pyroptosis-related changes. Mdivi-1 produced effects similar to those of luteolin, supporting the involvement of mitochondrial fission disruption. In vivo, luteolin inhibited tumor growth without obvious systemic toxicity. These findings indicate that luteolin suppresses PDAC progression by inhibiting RAS/ERK-dependent, DRP1-mediated mitochondrial fission, thereby inducing mitochondrial dysfunction and triggering pyroptosis.

Heart failure (HF) is a high-mortality condition driven by cardiomyocyte death, and ferroptosis is a critical contributor to myocardial injury in this regard. Tanshinone IIA (Tan-IIA), a bioactive component from Salvia miltiorrhiza, has been shown to protect the heart, but its role in HF-related ferroptosis remains unclear. This study investigated whether Tan-IIA ameliorates HF by inhibiting ferroptosis and its underlying mechanism. We evaluated cardiac function, fibrosis, ferroptosis markers (such as ROS, Fe[Formula: see text], GSH, xCT, and GPX4), and Sirt1/p53 signaling using both a mouse model of HF induced by ligation of the left anterior descending (LAD) coronary artery and oxygen-glucose deprivation (OGD)-treated H9c2 cells. Direct binding of Tan-IIA to Sirt1 was verified by molecular docking, CETSA, and DARTS. Tan-IIA improved cardiac function, reduced fibrosis and inflammation, decreased ROS/Fe[Formula: see text], increased GSH, and upregulated xCT/GPX4 in vivo and in vitro. However, erastin reversed these effects. Tan-IIA upregulated Sirt1 and downregulated p53, while Sirt1 inhibition by EX527 abolished its cardioprotective and antiferroptotic actions. Tan-IIA ameliorates HF by inhibiting myocardial ferroptosis through the Sirt1/p53/GPX4 pathway thus in turn supports its potential clinical use in the treatment of HF.

Marked by high blood glucose and systemic metabolic dysfunction, type 2 diabetes mellitus (T2DM) is a significant health issue with a rapidly increasing worldwide prevalence. Recent studies have highlighted the gut microbiota as a key determinant of host metabolism, and identified that the composition and metabolic activity are closely linked to the development and progression of T2DM. This review comprehensively explores the intricate connection between T2DM and the gut microbiota, with a particular focus on how traditional Chinese medicine (TCM) can influence intestinal microbiota composition to manage disease. It also discusses the therapeutic potential of TCM, which includes natural medicinal extracts like baicalin, berberine, tetrahydrocurcumin, ginsenoside Rb1, ophiopogonin D, and resveratrol, compound formulations, and acupuncture, in regulating the intestinal microbiota ecosystem to manage T2DM. Although the current evidence suggests that these interventions may slow T2DM progression, most studies have been confined to animal models and early clinical trials which lack adequate clinical evidence to confirm their efficacy. This discrepancy has created an imbalance between theoretical and validated clinical applications. Building on existing research, future research should focus on large-scale clinical trials and advanced multi-omics studies to uncover the potential of TCM in managing T2DM through the gut microbiota.

Diabetic osteoporosis (DOP) is a serious skeletal complication of diabetes mellitus. Its pathogenesis is complex, and its clinical prevention and treatment face significant challenges. In recent years, ferroptosis - particularly mitochondria-associated ferroptosis, which is closely linked to mitochondrial dysfunction - has been identified as a key mechanism underlying osteoblast injury in DOP. A chronic high-glucose environment can induce mitochondrial oxidative stress, iron metabolic dysregulation, and a lipid peroxidation cascade, leading to failure of the antioxidant systems (e.g., the GPX4 and Nrf2 pathways) and ultimately resulting in ferroptosis of osteoblasts and disruption of bone homeostasis. Traditional Chinese medicine (TCM) offers the advantages of multi-target and holistic regulation in the prevention of DOP. Its therapeutic principle of "tonifying the kidney and replenishing essence, activating blood circulation and removing blood stasis" is highly consistent with modern strategies aimed at intervening in mitochondrial ferroptosis. This review examines the central role of mitochondrial ferroptosis in DOP and elucidates the pathogenesis of DOP from a modern biological perspective. Furthermore, it summarizes experimental evidence demonstrating that astragaloside IV, ginsenoside Rg1, puerarin, icariin, curcumin, and Zuogui Pills can effectively inhibit mitochondrial ferroptosis by activating the Nrf2/GPX4 antioxidant axis, improving mitochondrial function, and regulating iron homeostasis, thereby conferring bone-protective effects. In conclusion, targeting mitochondria-associated ferroptosis represents a promising therapeutic strategy for DOP, and TCM interventions that modulate this pathway offer a novel direction for drug development and clinical management.

Ferroptosis is a distinct form of regulated cell death (RCD) characterized primarily by iron dysregulation and lipid peroxidation. Emerging evidence indicates ferroptosis critically contributes to the initiation and progression of multiple cardiovascular diseases (CVDs), including atherosclerosis (AS), myocardial ischemia/reperfusion (MI/R) injury, myocardial infarction (MI), cardiomyopathy, and heart failure (HF). With growing recognition of ferroptosis's role in CVD pathogenesis, targeting ferroptosis has become a promising therapeutic strategy for these diseases. Traditional Chinese medicine (TCM) is characterized by multicomponent, multitarget, and holistic regulatory properties. Studies have demonstrated that bioactive constituents, such as 6-gingerol, curcumin, ginsenoside Rg3, paeoniflorin, and stachydrine, and TCM compound formulations, including Danshentongluo-Detoxification Decoction, Yiqi Fumai Injection, Shexiang Baoxin Pill, and Shensong Yangxin Capsule, exert cardioprotective effects. These effects operate by suppressing ferroptosis via the modulation of iron metabolism, inhibition of lipid peroxidation, and enhancement of anti-oxidant defense systems. Accordingly, this review systematically summarizes the molecular mechanisms of ferroptosis and its pathological roles in various CVDs while placing a particular emphasis on recent advances in TCM-based ferroptosis interventions. This summary provides theoretical insights and potential research strategies both for the prevention and treatment of CVD, and for the development of related therapeutics.

Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, plays a critical role in various diseases. Berberine, a bioactive compound from plants such as Coptis chinensis, tree turmeric, and barberry, exhibits bidirectional regulation of ferroptosis, but its systemic mechanisms remain unclear. This review summarizes berberine's effects through multiple signaling pathways, emphasizing context-dependent mechanisms, tissue-specific accumulation, and therapeutic potential. Relevant literature was retrieved from PubMed, Web of Science, CNKI, and ScienceDirect. Berberine modulates ferroptosis via iron homeostasis, lipid peroxidation, the System Xc[-]/GSH/GPX4 anti-oxidant system, and mitochondrial function, involving NRF2, p53, AMPK, PI3K/Akt, and MAPK pathways. It promotes ferroptosis in tumors and fibrotic diseases but inhibits it in cardiovascular, metabolic, and neurological disorders, alleviating tissue damage. Nano-delivery systems and structural optimization enhance bioavailability and targeting, demonstrating therapeutic efficacy and biosafety. Berberine's multi-target, bidirectional regulation shows promising clinical potential, warranting further mechanistic and delivery-focused studies.

Chronic atrophic gastritis (CAG) is a major precancerous lesion of gastric cancer, characterized by a high incidence rate, a protracted clinical course, and a well-documented risk of malignant transformation. Current Western medical treatments exert limited efficacy in reversing progressive gastric mucosal damage. In traditional Chinese medicine (TCM), CAG is categorized as expressing symptoms such as "stomachache" and "abdominal fullness," with the core pathogenesis defined as "spleen-stomach deficiency as the root, and qi stagnation, blood stasis, and damp-heat as the superficial manifestations." TCM confers distinct clinical advantages through therapeutic strategies which include invigorating the spleen and replenishing qi, clearing heat and resolving dampness, and promoting blood circulation to remove stasis. Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly recognized as a key driver of gastric mucosal injury and disease progression in CAG, and exerts its effects via nine core pathways including iron metabolism imbalance, glutathione (GSH) depletion, lipid peroxidation (LPO), mitochondrial dysfunction, and inflammatory responses. This review systematically elaborates on the molecular mechanisms of ferroptosis in CAG pathogenesis and comprehensively summarizes recent advances in how active ingredients derived from Chinese herbal medicines (such as baicalein, curcumin, tanshinone IIA, astragaloside IV) and classic compound formulas like Sijunzi Decoction, Banxia Xiexin Decoction, Moluodan, and Weifuchun regulate ferroptosis-related signaling pathways. It further highlights the multi-target, multi-pathway characteristics of TCM in alleviating oxidative damage and promoting mucosal repair. Ultimately, this review aims to elucidate the scientific basis of TCM-mediated ferroptosis regulation in CAG management, provide novel theoretical support for clinical practice, and guide future directions for drug research and development.

Angelica sinensis (Oliv.) Diels (A. sinensis), a perennial herb with a medicinal history spanning over two millennia, is widely recognized for its effects in nourishing blood, promoting circulation, regulating menstruation, and alleviating pain. As demonstrated by over 1572 articles published since 2016, research in this field has advanced rapidly. However, the most recent comprehensive review dates back to 2016, and lacks systematic coverage of pharmacological mechanisms, structure-activity relationships (SARs), and modern applications. As a result, much of the relevant knowledge has been fragmented across disciplines. This review addresses these gaps by providing a systematic synthesis of the botany, traditional uses, phytochemistry, pharmacology, safety, and applications of A. sinensis. Over 290 chemical constituents, which can be broadly categorized into volatile oils, organic acids, polysaccharides, phenylpropanoids, and flavonoids, have been identified from A. sinensisto date. Representative bioactive compounds, such as Z-ligustilide (Z-lig), ferulic acid, and angelica coumarin A, contribute significantly to its diverse biological activities. This review offers an in-depth, mechanism-based summary of its pharmacological properties, and places a particular emphasis on the SARs of key bioactive constituents. The scope of the review is further expanded to include emerging applications in functional foods, skincare, agriculture, and animal husbandry industries. This review integrates multidisciplinary advances to establish a comprehensive and mechanistically grounded framework. This framework aims in turn to guide evidence-based utilization, foster innovative applications, and support the sustainable global development of A. sinensis as a medicinal and functional resource. However, several challenges remain in current research. These include insufficient standardization of cultivation practices, limited high-quality clinical evidence, and the lack of internationally recognized quality standards. Future research should prioritize multicenter clinical trials, the elucidation of biosynthetic pathways, and the establishment of international quality standards in order to promote the sustainable global development of A. sinensis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, and chronic neuroinflammation. Current pharmacological interventions demonstrate limited therapeutic efficacy. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a pivotal regulator of oxidative stress and neuroinflammation, plays a critical role in AD pathogenesis. Recent studies have revealed that traditional Chinese medicines (TCMs) and their bioactive constituents can modulate the Nrf2 signaling pathway to mitigate oxidative stress, suppress neuroinflammation, enhance Aβ clearance, and reduce Tau protein phosphorylation. By doing so, TCMs exert multi-targeted anti-AD effects. This review systematically summarizes the mechanisms and recent advances concerning the active ingredients of Nrf2 pathway-modulating TCMs, herbal medicines, and TCM formulations for the prevention and treatment of AD. Furthermore, it critically evaluates current research limitations and prospects for future research directions to provide a theoretical foundation for the development of novel anti-AD therapeutics derived from TCMs.