Open research questions in Flavonoids in Medical Research

What the literature leaves open

• However, it should be emphasized that these mechanistic observations are derived predominantly from in vitro and animal studies, and their translational relevance in human PCa remains to be fully established. Although research interest in milk thistle- derived nutraceuticals has declined in recent years and robust clinical evidence remains limited, the available experimental literature still provides substantial evidence supporting their biological activity in PCa models.

  Silybum marianum-Derived Compounds in Prostate Cancer: Mechanisms of Action and Translational Potential · 2026 · DOI

• Conserved signaling pathways may therefore represent potential candidates for future cross‑species pharmacological investigation, particularly in livestock where species‑specific pharmaco‑ logical data remain limited [16,27,28].

  Integrated Network Pharmacology and Cross-Species Analysis Suggest a Potential Role of AKT1/HIF1A Axis in Shuanghuanglian for Pneumonia–Myocarditis Comorbidity · 2026 · DOI

• remains is In summary, although herbal drugs have great potential as multi-targeted and safer alternatives for the management of fibrosis, their successful translation into evidence-based clinical practice remains constrained by several important scientific and translational challenges. These include the lack of standardization of raw materials, Polyherbal Unani Formulation (PUF) preparations, insufficient characterization of active phytochemical constituents, and limited understanding of the molecular mechanisms through which the complete formulation exerts its therapeutic effects.

  Molecular insights of a Unani formulation in targeting fibrosis-associated diseases · 2026 · DOI

• These include the lack of standardization of raw materials, Polyherbal Unani Formulation (PUF) preparations, insufficient characterization of active phytochemical constituents, and limited understanding of the molecular mechanisms through which the complete formulation exerts its therapeutic effects.

  Molecular insights of a Unani formulation in targeting fibrosis-associated diseases · 2026 · DOI

• 2 Baicalein recognition is organized through mixed Arms II and III engagement rather than Tyr473-centered anchoring and The interaction pattern explains how baicalein can remain lacking persistent canonical AF-2 pocket-associated while anchoring.

  Molecular dynamics analysis of a docking-derived baicalein–PPARγ ligand-binding-domain model suggests a pocket-associated AF-2-anchor-silent ensemble · 2026 · DOI

• Future studies will focus on identifying the specific molecular mechanisms involved, including the role of protein post-translational modifications and protein- protein interactions in this process, to further clarify the molecular mechanism of SCU in antagonizing I/R injury and provide more evidence for the application of SCU in the prevention and treatment of I/R injury. To address these limitations, in our future experiments, we plan to directly isolate endothelial cells from blood vessels and confirm the expression of the proteins of interest in endothelial cells using techniques such as flow cytometry and Western blot to further validate our findings and provide stronger evidence for our conclusions; Thirdly The present study was limited by the fact that the molecular pathway of SCU-mediated upregulation of CTSD in endothelial cells was not explored further.

  Scutellarin ameliorates ischemia/reperfusion-mediated endothelial dysfunction by upregulating cathepsin D expression to rescue autophagy-lysosomal function · 2025 · DOI

• S. baicalensis, a natural medicinal plant with abundant therapeutic properties, has a variety of bioactive compounds, such as flavonoids, terpenoids, and polysaccharides. Notably, flavonoids such as baicalein and wogonin, along with their glycosides, have been demonstrated to exert significant renoprotective effects. For AKI, S. baicalensis exerts robust renoprotective actions through multi-target synergistic mechanisms that include the inhibition of MAPKs/NF-κB inflammatory signaling pathways, activation of the an- tioxidant defense system, regulation of the Bcl-2/Bax-SIRT1/p53 apoptosis pathway, and suppression of ferroptosis mediated by 12-lipoxygenase. Among these mechanisms, the modulation of ferroptosis represents a novel therapeutic avenue for AKI treatment. In CKD, the active components derived from S. baicalensis can enhance renal function by delaying the progression of fibrosis through the inhibition of the TGF-β/Smad signaling pathway and cell injury induced by oxidative stress. Nevertheless, current evidence primarily origi- https://doi.org/10.3390/biom16010064 Biomolecules 2026, 16, 64 12 of 19 nates from animal studies; therefore, further clinical validation is essential to confirm their translational potential for therapeutic applications. Despite these promising findings, several significant challenges persist within the current research landscape. First, current studies predominantly concentrate on flavonoids as the bioactive ingre- dients from S. baicalensis for the treatment of kidney disease, with insufficient exploration of other structurally diverse components such as terpenoids and polysaccharides. Second, there is a substantial body of research focusing on the inhibitory effects on renal tubular injury, but there is a lack of investigations concerning glomerular injury. Thirdly, the in- tricate regulatory network underlying the synergistic nephroprotective effects of multiple components necessitate further elucidation through systems biology approaches. Fourth, the strategy for clinical evaluation of the active components of S. baicalensis has yet to be established. To address these challenges, future research is necessary to systematically explore the renoprotective effects and underlying mechanisms. Firstly, the renoprotective effects of other types of compounds in S. baicalensis, such as terpenoids and polysaccharides, should be further explored. Secondly, the integration of multi-omics technologies, including spatial transcriptomics and protein–protein interaction network analysis, can be employed to facilitate a comprehensive mechanistic understanding of the “component–target–pathway” regulatory network. Thirdly, advanced models such as organoids and organ-on-a-chip platforms should be used to enhance the translational value in new drug development. Furthermore, special attention should be directed towards creating novel nano-drug deliv- ery systems to increase the therapeutic effects of molecules from S. baicalensis to overcome its bioavailability limitations through formulation innovations. These systematic and multi- disciplinary approaches will effectively promote the application of S. baicalensis in treating kidney disease. Author Contributions: Conceptualization, H.C., Y.F. and K.J.; methodology, H.C., X.Y., F.D. and L.H.; formal analysis, H.C., X.Y. and F.D.; data curation, Y.X., J.C., Y.C. and R.W.; resources, H.C. and X.Y.; writing—original draft preparation, X.Y. and F.D.; writing—review and editing, H.C., Y.F. and K.J.; supervision, H.C. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by National Natural Science Foundation of China (No. 82460731, 82003836), Key R&D Plan Project of Ningxia (No. 2024BEG01006, 2021BEB04080), and Research Project of Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Ningxia Medical University (No. KFKT202313). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author. Acknowledgments: During the preparation of this manuscript, the authors used ERNIE-4.5 and DeepSeek-R1 (Open AI) in the writing process to improve readability. The authors have reviewed and edited the output and take full responsibility for the content of this publication. Conflicts of Interest: The authors declare no conflict of interest.

  Scutellaria baicalensis Georgi: A Promising Source of Bioactive Molecules for Kidney Disease Therapy · 2025 · DOI

• and research tolerance compliance. Clinical Cardiovascular disease is currently the leading cause of death. Its onset is related to a variety of factors, such as smoking and obesity. Based on the complexity of the condition of CVDs, a variety of therapeutic strategies for CVDs have been proposed. One of the most often utilized regimens for CVDs treatment is medication combination, which reduces the single drug dose while improving has patient demonstrated the efficacy of Chinese medicine as an alternative therapy for CVDs when combined with western medications. Tanshinone IIA combined with atorvastatin effectively attenuated atherosclerosis in rats. When nimodipine and total saponins from Panax ginseng were taken together, the damage from hypertensive cerebral hemorrhage was lessened. In previous studies, Baicalin, an extract from S. baicalensis, has demonstrated anti-inflammatory, antioxidant, and other cardiovascular system benefits. This suggests that baicalin has strong potential to be one of the options for combination medications. Studies on baicalin in combination for the treatment of CVDs have not, however, been conducted. Therefore, to be further studied. the strategy of combining baicalin needs We summarize the mechanism of action of baicalin in this including its anti-inflammatory and antioxidant effects; innate article, inhibition of endothelial cell apoptosis; modulation of

  Pharmacological mechanisms by which baicalin ameliorates cardiovascular disease · 2024 · DOI

• it was From the ADME-related characteristics of baicalein, found that baicalein demonstrates good drug-likeness and warrants further research (Table 1).

  Mechanism of baicalein in treatment of castration-resistant prostate cancer based on network pharmacology and cell experiments · 2024 · DOI

• However, the main components of OP remain unknown. Data on the effects of other elicitors (beyond exopolysaccharides and exoproteins) from the culture filtrates of endophytic fungi on the synthesis of plant secondary metabolites are lacking.

  Effects of elicitors from culture filtrate of Fusarium solani CL105 on flavonoid production of Scutellaria baicalensis calli · 2024 · DOI

• While preclinical data strongly support their anti- cancer potential, robust clinical validation is still lacking. Despite these promising preclinical findings, clinical evidence remains limited and largely exploratory.

  Silybum marianum-Derived Compounds in Prostate Cancer: Mechanisms of Action and Translational Potential · 2026 · DOI

• However, further mechanistic investigations and in vivo studies are warranted to elucidate their precise modes of action and support future clinical translation.

  Cytotoxicity of Mineral Pitch against HEp-2 and Saos 2 cell lines: in vitro and in silico studies · 2026 · DOI

• Future research should focus on identifying optimal hesperidin doses that maximize anti-inflammatory benefits while minimizing pro-oxidant risks, and on elucidating the molecular mechanisms underlying these complex dose-dependent effects.

  The Effect of Hesperidin on Inflammatory Response and Oxidant–Antioxidant Systems in Benzo[a]pyrene-Exposed Non-Small Cell Lung Cancer (A549) Cells · 2026 · DOI

• the upstream mechanisms responsible for BPA-induced FN1 upregulation were not investigated.

  FN1-associated cavernous endothelial remodeling induced by bisphenol A: relevance to erectile dysfunction and attenuation by baicalin · 2026 · DOI

• One limitation of this study is the reliance on MCF-7 cells to validate our hypothesis.

  Identifying Baicalein as a Key Bioactive Compound in XueBiJing Targeting KEAP1: Implications for Antioxidant Effects · 2025 · DOI

• Consequently, including females in this initial study would have required increasing the number of animals, a step not justified from a bioethical standpoint for this preliminary ex- ploratory design; nevertheless, future studies should address the chronic effects of chrysin and their relationship to pharmacological tolerance in female rats, taking into account the influence of the estrous cycle phase.

  Chronic Chrysin, but Not Diazepam, Induces Anxiolytic-like Effects Without Behavioral Tolerance · 2026 · DOI

• Conflicting results are observed across different disease models, particularly between tumor models and other disease models.

  Recent Advances in the Therapeutic Effects and Molecular Mechanisms of Baicalin · 2025 · DOI

• Future studies are warranted to explore the applicability of baicalein in human aging to pave the way for innovative antiaging supplement formulations.

  Baicalein Enhances Longevity and Healthspan of C. elegans Through the Insulin/IGF‐1 Signaling Pathway · 2025 · DOI

• Despite its therapeutic potential, the full scope of its effects on healthspan and longevity remains unexplored.

  Baicalein Enhances Longevity and Healthspan of C. elegans Through the Insulin/IGF‐1 Signaling Pathway · 2025 · DOI

• BACKGROUND & AIMS: Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is closely linked to liver fibrosis, yet effective preventive therapies remain elusive.

  Oroxyloside inhibits liver fibrosis and hepatocarcinogenesis dependent on hepatocyte-specific knockout of Atg5 · 2025 · DOI

• For the management of ophthalmic diseases, Scutellarin (Scu) has demonstrated neuroprotective potential, but its efficacy and mechanisms in glaucoma remain unexplored.

  Scutellarin Protects Retinal Ganglion Cells in Glaucoma by Targeting the Hsp90aa1-MAPK Pathway to Inhibit Apoptosis · 2025 · DOI

• However, the in-vivo pharmacodynamic material basis for this formula remains unclear.

  Integrated pharmacokinetic properties and tissue distribution of multiple active constituents in Qing-Yi Recipe: A comparison between granules and decoction · 2024 · DOI

• However, it remains unclear whether baicalein alleviates obesity-induced cardiac damage through the UPRmt.

  Baicalein ameliorated obesity-induced cardiac dysfunction by regulating the mitochondrial unfolded protein response through NRF2 signaling · 2024 · DOI

• While strides have been made in overcoming pharmacokinetic hurdles, further research into apigenin's clinical effectiveness and bioavailability from herbal supplements remains imperative for its widespread utilization in preventive medicine.

  A comprehensive review of apigenin a dietary flavonoid: biological sources, nutraceutical prospects, chemistry and pharmacological insights and health benefits · 2024 · DOI

• Despite its extensive research and recognized nutraceutical value, its therapeutic application remains underexplored, necessitating further clinical investigations.

  A comprehensive review of apigenin a dietary flavonoid: biological sources, nutraceutical prospects, chemistry and pharmacological insights and health benefits · 2024 · DOI

Most-cited papers in Flavonoids in Medical Research

• Flavonols and Flavones as Potential anti‐Inflammatory, Antioxidant, and Antibacterial Compounds · Oxidative Medicine and Cellular Longevity · 2022 · 423 citations
• Absorption, metabolism and bioavailability of flavonoids: a review · Critical Reviews in Food Science and Nutrition · 2021 · 397 citations
• Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis · Computers in Biology and Medicine · 2022 · 378 citations
• Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. · Environmental Health Perspectives · 2003 · 283 citations
• Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro · Journal of Enzyme Inhibition and Medicinal Chemistry · 2021 · 267 citations
• Review of the effects of vitexin in oxidative stress‐related diseases · Food Science & Nutrition · 2020 · 146 citations
• Apigenin: A Bioflavonoid with a Promising Role in Disease Prevention and Treatment · Biomedicines · 2024 · 119 citations
• Fisetin: An anticancer perspective · Food Science & Nutrition · 2020 · 115 citations
• Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers and animal models · Acta Pharmacologica Sinica · 2007 · 113 citations
• Anticancer, antioxidant, ameliorative and therapeutic properties of kaempferol · International Journal of Food Properties · 2023 · 104 citations

Most recent work

• Exploring the therapeutic potential of baicalin against MCF-7 breast cancer cells: biochemical, in vitro, and computational perspectives · Frontiers in Pharmacology · 2026
• Chemoproteomics identifies STAT3 as a key target of baicalin in ameliorating liver fibrosis · National Science Review · 2026
• Ocular and Systemic Pharmacokinetics of Baicalein and Baicalin After Intravitreal Injection and Oral Administration in Mice · Pharmaceutics · 2026
• ROS-responsive self-assembly of baicalin-peptide as a “Molecular Latch” to break the endothelial-to-mesenchymal transition-inflammation loop in atherosclerotic plaques · Journal of Controlled Release · 2026
• Scutellaria baicalensis Georgi as a potential therapeutic drug intervention in ulcerative colitis: Mechanisms of action and clinical trials · World Journal of Gastroenterology · 2026
• Carrier free oral Co-delivery of atorvastatin via baicalein-copper-network for atherosclerosis therapy through senescence reversal and multi-mechanistic synergy · Bioactive Materials · 2026
• Fisetin-loaded nanoparticles as a novel approach for cholesterol regulation in hypercholesterolemia: targeting the ASGR1-mediated mTORC1/AMPK pathway · Journal of Nanobiotechnology · 2026
• Medicinal Plants for Overcoming Drug Resistance in Cervical Cancer · Biology · 2026
• IL-24 amplifies baicalein-induced immunogenic cell death in ovarian cancer by boosting endoplasmic reticulum stress · Journal of Ovarian Research · 2026
• Baicalein Alleviates Cardiomyocyte Hypoxia Injury via ESR1‐Dependent Modulation of BAX/BCL‐XL Balance · Phytochemical Analysis · 2026

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