Colorectal cancer (CRC) frequently develops resistance to 5-fluorouracil (5-FU)-based chemotherapy, which remains a major obstacle to successful treatment. Ginseng-containing Sijunzi Decoction (SJZD), a classical Traditional Chinese Medicine formula, has demonstrated antitumor activity; however, whether and how SJZD enhances 5-FU sensitivity remains largely unclear. In this study, SJZD-containing serum was prepared and administered to 5-FU-resistant CRC cell lines (HCT116/5-FU and SW480/5-FU). Chemosensitivity was evaluated using Cell Counting Kit-8 (CCK-8) and Calcein-AM/propidium iodide (PI) staining assays, while ferroptosis was assessed by measuring oxidative stress-related indicators, including malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and intracellular ferrous iron (Fe[Formula: see text]) levels. In addition, a BALB/c nude mouse xenograft model was established to validate the synergistic antitumor effects of SJZD and 5-FU in vivo. Protein-protein interactions and ubiquitination were examined by co-immunoprecipitation and in vitro ubiquitination assays. Our results demonstrated that SJZD markedly enhanced the sensitivity of resistant CRC cells to 5-FU by inhibiting cell proliferation and promoting ferroptosis both in vitro and in vivo. In the xenograft model, combined treatment with SJZD and 5-FU produced significantly greater reductions in tumor volume and tumor weight than treatment with 5-FU alone. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively abolished the chemosensitizing effect of SJZD, indicating that ferroptosis is required for SJZD-mediated reversal of 5-FU resistance. Mechanistically, SJZD suppressed the expression of the E3 ubiquitin ligase membrane-associated ring finger protein 3 (MARCHF3), thereby inhibiting the ubiquitination and proteasomal degradation of arachidonate 15-lipoxygenase (ALOX15), a critical regulator of ferroptosis. Rescue experiments further demonstrated that ALOX15 silencing or MARCHF3 overexpression significantly attenuated SJZD-induced ferroptosis and reversed its sensitizing effect on 5-FU-resistant CRC cells. Collectively, these findings demonstrate that SJZD enhances the chemosensitivity of CRC cells to 5-FU by activating ferroptosis through regulation of the MARCHF3/ALOX15 axis. This study provides mechanistic insight into the antitumor activity of SJZD and highlights its potential as a promising adjuvant strategy for overcoming 5-FU resistance in CRC.

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation. This concept reshapes our understanding of tissue degenerative lesions and oncogenesis. Icariin (ICA) is an isoprenyl flavonol glycoside derived from plants of the genus Epimedium. Acting as a bidirectional regulator of this pathway, it precisely modulates cellular sensitivity to ferroptosis across distinct disease states. This review systematically synthesizes literature from PubMed, ScienceDirect, Web of Science, and Google Scholar (2015-2025). Search keywords included "Icariin", "ferroptosis", "pharmacological mechanism", "pharmacokinetics" and "toxicology", while excluding conference abstracts, non-English studies, and reports lacking raw data. We systematically elucidated the role of ICA across a continuous "mechanism-treatment-metabolism" spectrum: in neurodegenerative disease models, ICA exerts an anti-oxidant effect to maintain cellular homeostasis, whereas in drug-resistant cancer cells, it functions as a pro-oxidant, promoting the elimination of malignant cells. This context-dependent effect is primarily attributed to its modulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) axis, which serves as the critical "molecular switch" of redox homeostasis. Beyond direct signaling, ICA functions as a natural precursor. Its safety profile and therapeutic window are governed by the metabolic network, potentially conferring advantages over synthetic inhibitors. Although low systemic bioavailability limits clinical translation, nanodelivery systems and synthetic biology strategies offer viable approaches for optimizing its metabolic profile. Ultimately, ICA provides an exquisite molecular blueprint, charting a course for the development of ferroptosis-targeted therapies that can precisely sense and adapt to the microenvironments of complex diseases.

Alzheimer's disease (AD), a progressive neurodegenerative disease with a rising global prevalence, is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, inflammation, oxidative damage, and neuronal apoptosis. Studies have increasingly recognized epigenetic modifications as key regulators in the development of AD. Epigenetic modifications, particularly histone acetylation, are increasingly recognized as critical regulators of cell survival and AD pathogenesis. Although artemisinin (ART) exhibits potent anti-oxidative, anti-inflammatory, and neuroprotective properties, its impact on histone acetylation in AD remains uncharacterized. This study investigated whether ART regulates histone acetylation to confer neuroprotection and rescue behavioral deficits in Alzheimer's disease models. Using SH-SY5Y cells, primary neurons, and 3xTg-AD mice, we found that ART restores histone acetylation homeostasis by enhancing histone H4 acetylation. Mechanistically, this effect is driven by the activation of the CaMK IV/PKA-CREB signaling cascade. Treatment with ART reduced ROS, improved mitochondrial function, decreased Aβ1-42 deposition, and suppressed neuronal apoptosis. However, these beneficial effects were abolished by PKA or CaMK IV inhibitors. Consequently, ART treatment significantly reduced reactive oxygen species (ROS) generation, restored mitochondrial function, decreased Aβ1-42 deposition, suppressed neuronal apoptosis, and alleviated AD-like neuropathology and cognitive deficits. Crucially, the neuroprotective and epigenetic benefits of ART were entirely abolished by pharmacological inhibitors of PKA or CaMK IV. This study is the first to demonstrate that artemisinin ameliorates AD pathology and behavioral impairments via the CaMK IV/PKA-CREB-Ace-H4 axis, establishing ART as a promising therapeutic candidate for epigenetic intervention in AD.

Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer characterized by poor prognosis and limited therapeutic options, remains a major clinical challenge. Bufalin, a principal bioactive component of Venenum Bufonis, exhibits potent anticancer activity against breast cancer. Nevertheless, the precise molecular mechanism by which bufalin triggers ferroptosis in TNBC cells remains poorly elucidated. In the present study, both in vitro and in vivo investigations were performed. Cellular ferroptosis was comprehensively evaluated by detecting intracellular Fe[Formula: see text], ROS, MDA, and reduced GSH levels, together with ultrastructural observation under transmission electron microscopy. Transcriptome sequencing combined with bioinformatic analysis was applied to screen the core regulatory mechanism of bufalin-induced ferroptosis in TNBC, and subsequent molecular biological experiments were conducted for further validation. The results demonstrated that bufalin significantly suppressed the proliferation and migration of TNBC cells. Bufalin treatment markedly increased Fe[Formula: see text], ROS, and MDA levels, depleted intracellular GSH, and induced mitochondrial shrinkage and cristae damage. Transcriptome analysis identified the NRF2/HO-1/GPX4 signaling axis as the central pathway mediating the pharmacological effect of bufalin. Mechanistically, bufalin downregulated the expression of NRF2, HO-1, SLC7A11, and GPX4, whereas it upregulated KEAP1 expression. In vivo studies verified that bufalin effectively inhibited tumor growth with no obvious systemic toxicity. Moreover, bufalin decreased the expression of GPX4 and Ki-67, increased the number of TUNEL-positive cells, and blocked the activation of the NRF2/HO-1/GPX4 pathway in tumor tissues. In conclusion, bufalin induces ferroptosis in TNBC by inhibiting the NRF2/HO-1/GPX4 signaling pathway, thereby exerting antitumor effects. These findings indicate that bufalin serves as a promising therapeutic agent for TNBC treatment.

Panax notoginseng saponins (PNS), the chief saponin components of the traditional Chinese medicine Panax notoginseng, are known to ameliorate the outcomes of ischemic stroke (IS), primarily by mitigating inflammatory responses, enhancing microcirculation, and modulating oxidative stress. Damage to brain microvascular endothelial cells (BMECs) and BMECs' ferroptosis are critical steps in cerebral ischemia-reperfusion injury (CIRI), a process in which neutrophil extracellular traps (NETs) have been shown to induce BMECs injury, thereby aggravating CIRI. We aimed to investigate the regulatory effects of PNS on NETs and BMECs' ferroptosis following CIRI and evaluate its therapeutic efficacy in brain injury intervention. In this study, Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and the BMECs were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). These models were pretreated with PNS or the NETs-degrading agent DNase I, and the ensuing changes in key proteins, NETs-related markers, inflammatory factors, and ferroptosis-related indicators were assessed using Western Blotting or specific assay kits. Finally, neurological injury was assessed by neurological function scores and triphenyl tetrazolium chloride staining, while cell viability was evaluated using the Cell Counting Kit-8 (CCK-8) assay. In the rat models, PNS and DNase I markedly reduced the levels of key NETs biomarkers, related inflammatory factors, as well as MCAO/R-triggered ferroptosis, thereby mitigating brain injury. PNS treatment effectively suppressed NETs-induced ferroptosis in BMECs in vitro, thereby alleviating cell injury. This study demonstrated that PNS alleviates CIRI by inhibiting NETs and BMECs' ferroptosis. Mechanistically, PNS suppresses NETs, thereby suppressing ferroptosis. Collectively, these findings support a pharmacological rationale underlying the clinical treatment of IS.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and progressive joint damage. This study investigated the role of microRNA-223 (miR-223) in RA and evaluated the therapeutic effects of triptolide (Tri), a diterpenoid epoxide derived from the traditional Chinese medicinal herb Tripterygium wilfordii. A collagen-induced arthritis (CIA) mouse model was used to assess the effects of Tri and methotrexate (MTX). Micro-computed tomography, histological staining, enzyme-linked immunosorbent assay, flow cytometry, RT-qPCR, and western blot analysis were used to evaluate joint damage, inflammation, cytokine profiles, miR-223 expression, and the function of CREBZF, a downstream target of miR-223. CIA mice exhibited marked joint inflammation, swelling, bone erosion, and inflammatory cell infiltration, increased pro-inflammatory cytokine levels, and elevated miR-223 expression. Tri and MTX ameliorated these abnormalities and protected against bone erosion and inflammation. Tri suppressed the disease-associated elevation of miR-223, attenuated pathological fibroblast-like synoviocyte (RA-FLS) phenotypes, and shifted cytokine profiles toward an anti-inflammatory state. Dual-luciferase reporter and AGO2-RIP-qPCR assays supported direct regulation of CREBZF by miR-223. Tri restored CREBZF expression and inhibited NF-κ B signaling, thereby reducing RA-FLS proliferation and promoting apoptosis. These findings indicate that Tri ameliorates RA, at least partly, through the miR-223/CREBZF axis and identify this pathway as a potential therapeutic target.

Berberine (BBR), the core alkaloid of the traditional Chinese medicine Coptis chinensis (Huanglian), exhibits a notable pharmacological paradox: it possesses an oral bioavailability of less than 1% yet exerts broad therapeutic effects across the full spectrum of liver diseases, from metabolic dysfunction-associated steatotic liver disease (MASLD) through fibrosis to hepatic malignancies. This review constructs an integrated mechanistic framework to interpret BBR's holistic pharmacological characteristics, which distinguish it from conventional single-target drugs. In MASLD, BBR engages a convergent AMPK-SIRT-Nrf2 network to ameliorate insulin resistance, lipid dysregulation, oxidative stress, and hepatic inflammation. Combined with the complementary actions of its bioactive metabolites, it achieves parent-metabolite coordinated efficacy that embodies the holistic principle of traditional Chinese medicine. In liver fibrosis, BBR may block hepatic stellate cell activation via the TGF-β1/Smad3 pathway and eliminate activated HSCs through multiple programmed cell death pathways, particularly ferroptosis, which may overcome apoptosis resistance. In hepatic malignancies, BBR suppresses tumor progression, metastasis, and chemoresistance via apoptotic, ferroptotic, and immunomodulatory mechanisms. Current clinical evidence validates its metabolic benefits in MASLD, whereas clinical data regarding fibrosis and hepatic malignancies remain insufficient. Improving its poor bioavailability through structural modification and nanocarrier delivery is critical for clinical translation. This review provides a modern pharmacological rationale for the clinical application of Coptis chinensis-based formulas against progressive liver diseases.

Myocardial infarction (MI) necessitates the promotion of angiogenesis to improve prognosis. Panax quinquefolius saponins (PQS), bioactive constituents of a medicinal and edible homologous plant, are known for their cardiovascular benefits, but their epigenetic mechanisms in post-MI angiogenesis remain unclear. In this study, PQS was obtained through a water extraction method followed by stepwise enrichment via ethanol elution. Surgical ligation of the left anterior descending (LAD) coronary artery was performed to establish an MI model in male C57BL/6 mice. The therapeutic effects on MI in each group were assessed through histopathological staining and echocardiography. The therapeutic effects of PQS on hypoxic human umbilical vein endothelial cells (HUVECs) were evaluated using tube formation assays, scratch assays, CD31 immunofluorescence, and Western blot (WB). Network pharmacology analysis, Bisulfite Sequencing PCR (BSP) detection, PCR, and WB were utilized to examine the influence of DNMT3b on Notch1 methylation. Cellular Thermal Shift Assay (CETSA) and Co-Immunoprecipitation (Co-IP) assays were employed to ascertain the binding interaction and stability between PQS and DNMT3b. Here, we demonstrate that PQS directly binds DNMT3b, thereby reversing aberrant DNA methylation at the Notch1 promoter and activating the Notch1/ubiquitin-specific protease 5 (USP5)/signal transducer and activator of transcription 3 (STAT3) signaling axis, thereby enhancing endothelial cell migration, tube formation, and angiogenesis in MI models. Ginsenoside Rc, ginsenoside Rh4, and vinaginsenoside R1 were identified as the key active components with the strongest DNMT3b binding affinity and angiogenic activity, with ginsenoside Rc demonstrating the most significant therapeutic effects. These findings reveal a novel epigenetic mechanism and confirm that PQS, particularly ginsenoside Rc, is a highly promising bioactive compound for promoting angiogenesis following MI.

Inflammation is a pathological process central to many chronic diseases. Conventional anti-inflammatories, including NSAIDs and corticosteroids, are limited by adverse effects and suboptimal efficacy with long-term use. Ginsenosides from Panax ginseng have emerged as promising multi-target candidates with favorable safety profiles. This review systematically summarizes recent advances in research on the anti-inflammatory pharmacological effects and molecular mechanisms of ginsenosides, with particular emphasis on Rg1, Rb1, Rd, Re, and Rg3. Recent literature was collected and analyzed, and network pharmacology and bioinformatics approaches were employed to predict therapeutic targets and regulatory networks. Core anti-inflammatory mechanisms include suppression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and NF-κB signaling; modulation of TLR4/NF-κB and NLRP3 inflammasome activity; regulation of MAPK (ERK, JNK, and p38) phosphorylation; activation of Nrf2/HO-1 and Hippo-YAP/TAZ pathways; inhibition of COX-2 and iNOS expression; regulation of macrophage polarization; and modulation of membrane permeability and ion exchange. This study elucidates the association between ginsenosides and various inflammatory diseases, systematically consolidating their diverse molecular mechanisms underlying their treatment of typical inflammatory conditions. By integrating modern techniques such as network pharmacology and molecular docking, this review deepens our understanding of the efficacy of ginsenosides in the management of inflammatory diseases. It provides critical insights for further exploration of ginsenosides' pharmacological actions, the development of novel anti-inflammatory drugs, and the interpretation of the modern scientific basis underlying TCM concepts such as ginseng's "restorative and stabilizing" properties.

Phytoestrogens derived from natural products have emerged as potential alternatives to hormone replacement therapy (HRT) for alleviating menopausal symptoms with reduced adverse effects. However, the therapeutic potential and mechanistic basis of flaxseed-derived lignan secoisolariciresinol diglucoside polymer (SDGP) remain largely unexplored. This study aimed to investigate the synergistic effects of SDGP and a linusorb mixture (LOMIX) on menopausal symptoms and to elucidate their underlying molecular mechanisms. Estrogen receptor (ER) activation was evaluated using ERE-luciferase reporter assays and Western blot analysis in MCF-7 cells. Anti-osteoclastogenic effects were assessed in RANKL-induced RAW264.7 cells. An ovariectomized (OVX) rat model was used to examine in vivo efficacy on reproductive tissues and bone metabolism. Co-treatment with SDGP and LOMIX synergistically enhanced ER[Formula: see text]/ER[Formula: see text] phosphorylation and Akt activation, leading to increased transcription of ER target genes. The combination also suppressed osteoclast differentiation by inhibiting NF-[Formula: see text]B and MAPK signaling pathways, including c-Fos and NFATc1. In OVX rats, oral administration of the mixture restored vaginal cornification and uterine morphology, and significantly improved trabecular bone structure and bone mineral density. Notably, these effects were achieved without significant alterations in circulating estrogen, FSH, or LH levels. The combination of SDGP and LOMIX alleviates menopausal symptoms through non-hormonal activation of ER signaling and inhibition of osteoclastogenesis. These findings suggest a promising phytotherapeutic strategy for managing postmenopausal disorders with reduced risk of hormone-related side effects.

Ginsenoside Rg2 (G-Rg2) is a key protopanaxatriol-type saponin from Panax ginseng. Increasing evidence has shown that G-Rg2 exerts pharmacological effects such as neuroprotection, immune regulation, anti-inflammation and inhibition of tumor proliferation by reducing inflammatory response, blocking apoptotic cascade and regulating autophagic flow. In terms of mechanism of action, the diverse biological effects of G-Rg2 result from its background-dependent regulation of key intracellular signaling pathways such as AMPK, MAPK, NF-[Formula: see text]B and PI3K-AKT-mTOR, which are interconnected to form a complex regulatory network. This plasticity in pathway regulation confers bidirectional pharmacological properties of G-Rg2, which induces apoptosis through inhibition of the PI3K-AKT-mTOR pathway in MCF-7 breast cancer cells, whereas it activates the same pathway to promote cell survival in cardiomyocytes and neurons under ischemic conditions. Metabolomics and multiomics studies in animal models suggest that G-Rg2 regulates metabolic networks and multiple signaling pathways simultaneously in a complex disease environment, suggesting that G-Rg2 is most likely a network-level regulatory mode rather than a linear single-target action. The poor oral bioavailability, rapid systemic clearance, stereochemical complexity due to the 20(R)/20(S) isomers, and insufficient long-term safety data of G-Rg2 have hindered its translation into clinical trials. Based on existing mechanism-related research on G-Rg2, this review proposes a network-based regulatory framework and offers specific suggestions to enhance the bioavailability and targeting of G-Rg2, providing actionable directions for its clinical translation.

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 ApcMin/[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 ApcMin/[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.