Next Article in Journal
Impact of Anti-HER2 Therapies on Overall Survival in Patients with HER2-Positive Metastatic Breast Cancer: Focusing on Intracranial Efficacy of Emerging Treatments
Previous Article in Journal
High-Intensity Focused Ultrasound in Dermatology: A Review with Emphasis on Skin Cancer Management and Prevention
Previous Article in Special Issue
The Targeted Inhibition of Histone Lysine Demethylases as a Novel Promising Anti-Cancer Therapeutic Strategy—An Update on Recent Evidence
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 17
Issue 21
10.3390/cancers17213519
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

SH003 as a Redox-Immune Modulating Phytomedicine: A Ferroptosis Induction, Exosomal Crosstalk, and Translational Oncology Perspective

by
Moon Nyeo Park
1,
Md. Maharub Hossain Fahim
1,
Han Na Kang
2,
Hanul Bae
1,
Amama Rani
1,3,
Fahrul Nurkolis
4,5,
Trina E. Tallei
6,7,
Seong-Gyu Ko
1,8,* and
Bonglee Kim
1,8,*
1
Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
2
KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
3
Department of Zoology, University of Azad Jammu and Kashmir, Muzaffarabad 13100, Pakistan
4
Master of Basic Medical Science, Faculty of Medicine, University Airlangga, Surabaya 60115, Indonesia
5
Faculty of Science and Technology, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta 55281, Indonesia
6
Department of Biology, Faculty of Mathematics and Natural Sciences, University Sam Ratulangi, Manado 95115, Indonesia
7
Department of Biology, Faculty of Medicine, University Sam Ratulangi, Manado 95115, Indonesia
8
Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 05253, Republic of Korea
*
Authors to whom correspondence should be addressed.
Cancers 2025, 17(21), 3519; https://doi.org/10.3390/cancers17213519
Submission received: 3 October 2025 / Revised: 25 October 2025 / Accepted: 29 October 2025 / Published: 31 October 2025
(This article belongs to the Special Issue Feature Review for Cancer Therapy: 2nd Edition)
Browse Figures
Review Reports Versions Notes

Simple Summary

Cancer cells frequently evade cell death by suppressing ferroptosis and remodeling the immune microenvironment. SH003, a GMP-standardized herbal formulation, has shown promising preclinical and early clinical evidence of safety and efficacy. This review highlights how SH003 regulates redox signaling, induces ferroptotic vulnerability, and enhances antitumor immunity through STAT3/PD-L1 inhibition and macrophage/T cell activation. These network-level effects suggest SH003 as a representative phytomedicine that bridges traditional herbal therapy with modern precision oncology.

Abstract

Redox dysregulation, ferroptosis evasion, and immune suppression are major barriers in cancer therapy. SH003, a multi-herbal formulation standardized under GMP conditions and evaluated in early-phase clinical studies (NCT03081819; KCT0004770), demonstrated a favorable safety profile supporting its translational potential. Preclinical studies reveal that SH003 disrupts mitochondrial homeostasis, triggers endoplasmic reticulum stress apoptosis, and sensitizes resistant tumors to ferroptosis via suppression of the SLC7A11–GPX4 axis and NRF2 destabilization. In parallel, SH003 remodels tumor immunity by attenuating STAT3-driven PD-L1 signaling, promoting macrophage repolarization, and enhancing cytotoxic lymphocyte activity. Exosome-associated microRNAs further suggest SH003’s role in redox–immune communication, although functional validation is pending. Collectively, SH003 represents a clinically tested phytomedicine that integrates ferroptosis induction with immune modulation, offering a biomarker-informed approach to precision oncology.

Graphical Abstract

1. Introduction

Reactive oxygen species (ROS) function as pivotal regulators of cellular proliferation, survival programs, and immune activity. Malignant cells exploit ROS-dependent signaling to drive oncogenic transformation, sustain metabolic reprogramming, and adapt to therapeutic stress—a phenomenon often described as ROS addiction [1,2]. This dependency not only accelerates tumor progression but also creates exploitable liabilities. Attempts to therapeutically target ROS imbalance using conventional modulators have faced major obstacles, including insufficient pathway specificity, systemic toxicity, and the rapid development of adaptive resistance. Moreover, single-pathway inhibitors rarely succeed against the remarkable plasticity of redox-addicted malignancies such as triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).
SH003, a GMP-standardized and authenticated multi-herbal formulation derived from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii, has emerged as a representative example of next-generation phytomedicine [3,4]. Distinct from traditional small-molecule agents, SH003 modulates interconnected redox-sensitive processes—spanning mitochondrial ROS imbalance, endoplasmic reticulum (ER) stress, ferroptosis sensitization, and immune–exosome reprogramming—thereby functioning as a broad-spectrum platform for biomarker-informed interventions. In preclinical models, SH003 shows selective cytotoxicity in TNBC and NSCLC, and early-phase clinical evaluations (NCT03081819; KCT0004770) support a favorable safety profile, underscoring translational feasibility.
From a pharmacological standpoint, SH003 is among the earliest multi-herbal formulations formally evaluated in oncology, and its capacity to disrupt adaptive redox networks while remodeling immune dynamics highlights the potential of complex phytomedicines to advance precision oncology paradigms [5,6].
In first-in-human and multicenter Phase I studies, SH003 reached a maximum tolerated dose (MTD) of 4800 mg/day as monotherapy and was combinable with docetaxel without SH003-attributed dose-limiting toxicities; an expanded Phase I established safety up to 9600 mg/day, collectively indicating a favorable human safety window [7,8,9]. These trials also documented manufacturing traceability and rigorous authentication/quality-control procedures (e.g., marker-compound validation for decursin and formononetin), supporting reproducibility and clinical traceability expected for herbal formulations [7,8,9]. SH003 is composed of three major bioactive constituents: formononetin from Astragalus membranaceus, decursin from Angelica gigas, and cucurbitacin D from Trichosanthes kirilowii. Pharmacokinetic studies have shown that formononetin exhibits oral bioavailability of approximately 20–22% and a half-life of 2–4 h in rodents, primarily absorbed via passive diffusion and subject to rapid Phase II metabolism through UGT and CYP enzymes [10,11]. Decursin undergoes extensive first-pass hydrolysis to decursinol and hepatic oxidation, while cucurbitacin D displays high lipophilicity and CYP3A-dependent clearance [12]. These characteristics suggest that SH003’s constituents achieve multi-target systemic exposure with limited toxicity and predictable metabolic profiles.

Review Methodology

This article represents a comprehensive narrative review integrating mechanistic, preclinical, and early clinical evidence on SH003. Literature was collected from PubMed, Scopus, and Web of Science databases (2010–2025) using the Boolean combination of keywords ‘SH003’ AND (‘redox’ OR ‘ROS’ OR ‘ferroptosis’ OR ‘NRF2’ OR ‘STAT3’ OR ‘exosome’ OR ‘immune modulation’). Inclusion criteria comprised in vitro, in vivo, and clinical studies related to SH003 or its constituent compounds. Reviews, abstracts without mechanistic data, and unrelated natural products were excluded. Two authors independently screened the records to minimize bias.

2. Mechanistic Basis of SH003 in Redox Biology

2.1. Exosome-Immune Crosstalk and NRF2 Modulation

SH003-induced oxidative stress extends beyond intracellular compartments [13], influencing both exosomal cargo composition and immune regulatory pathways [14,15,16,17,18,19]. Exosomes carrying redox-sensitive miRNAs (miR-200c, miR-21, miR-210, miR-96) have been reported to modulate ROS buffering [20,21,22,23], ferroptosis sensitivity, and PD-L1 expression, thereby reshaping tumor–immune interactions [24]. In triple-negative breast cancer, tumor- and stroma-derived vesicles can activate the HDAC6/STAT3/PD-L1 signaling cascade, facilitating immune evasion [25]. In NSCLC models, SH003 ± docetaxel exerts synergistic antitumor effects via EGFR/STAT3 blockade; while exosome-based metabolomic signatures are best positioned as exploratory predictive biomarkers rather than proximal effectors of response, pending prospective immune-functional validation [26,27].
At the phytochemical level, individual SH003 constituents provide mechanistic plausibility: formononetin downregulates STAT3/PD-L1 signaling, baicalein promotes macrophage M1 polarization, and luteolin enhances CD8+ T-cell activity [6]. Current evidence, however, is largely inferred from constituent-based studies and awaits validation in SH003-specific systems. Beyond vesicle-mediated signaling, SH003 may also destabilize NRF2-driven antioxidant adaptation by modulating GSK3β activity, thereby providing KEAP1-independent regulation. This dual control suggests that SH003 could impair redox resilience in NRF2-hyperactivated tumors, offering opportunities for biomarker-guided patient stratification [28,29]. Collectively, SH003 exemplifies a phytomedicine capable of linking exosomal signaling, immune remodeling, and NRF2 regulation, underscoring its potential as a prototype redox–immune modulator in precision oncology (Figure 1).

2.2. Ferroptosis Induction

Ferroptosis is an iron-dependent form of regulated cell death, characterized morphologically by shrunken mitochondria and biochemically by glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation, and accumulation of lipid peroxides (LPOs) [30]. Although ferroptosis provides an attractive therapeutic target in cancer and inflammatory disorders, translation into the clinic remains challenging owing to tumor redox plasticity, the complexity of iron metabolism, and potential risks of off-target oxidative injury [30,31]. Experimental evidence demonstrates that genetic ablation of GPX4 results in embryonic lethality and triggers tissue-specific ferroptosis [30]. Likewise, disruption of glutathione S-transferase alpha 4 (GSTA4) enhances ferroptotic sensitivity in macrophages and prevents microbiota-driven colorectal tumorigenesis, highlighting ferroptosis as both a cytotoxic pathway and a regulator of immune–tumor interactions [31]. SH003 enforces ferroptotic vulnerability through multiple mechanisms: cucurbitacin-mediated inhibition of the SLC7A11–GPX4 axis, flavonoid-associated perturbation of iron handling [32,33,34], and NRF2 suppression by formononetin [35]. In contrast to single-pathway inducers, SH003 may amplify via multi-node interference, sensitizing ferroptosis-resistant tumor types such as triple-negative breast cancer (TNBC) and epidermal growth factor receptor (EGFR)-mutant NSCLC [36,37,38]. From a pharmacological perspective, ferroptosis induction by SH003 provides a rational approach to bypass therapeutic resistance and may serve as a foundation for biomarker-guided treatment strategies.

2.3. NRF2-KEAP1 and Redox Adaptation

The NRF2–KEAP1 signaling axis coordinates cellular antioxidant defenses and plays a central role in therapy resistance [39]. Numerous phytochemicals have been shown to modulate NRF2 activity in divergent ways [40], either sensitizing malignant cells to oxidative stress or attenuating adaptive survival mechanisms [41,42]. Through indirect, multi-target interference [43], SH003 redefines NRF2 not simply as a protective regulator but as a pharmacological vulnerability, effectively lowering cellular redox thresholds and thereby augmenting both ferroptotic and apoptotic susceptibility [35,41]. Given the high prevalence of NRF2 hyperactivation in KEAP1-mutant NSCLC—and its established links to immune escape and drug resistance—KEAP1/NRF2 genetic background emerges as a clinically relevant biomarker to stratify patients for SH003-based therapeutic strategies [44,45,46,47]. Prospective SH003 trials should pre-specify KEAP1/NFE2L2 genotype as a randomization/stratification covariate and include correlative endpoints—such as an NRF2 target-gene signature and serum SQSTM1 kinetics—to test whether NRF2-hyperactivated tumors derive preferential benefit from SH003-based regimens [48,49].

2.4. ER Stress and Apoptosis

The unfolded protein response (UPR) enables cells to adapt to oxidative disturbances; however, sustained or excessive activation redirects this signaling toward apoptosis [50]. SH003 constituents, including decursin [51,52] and hispidulin, promote this pro-apoptotic branch through the PKR-like ER kinase (PERK)–eukaryotic initiation factor 2α (eIF2α)–activating transcription factor 4 (ATF4)–C/EBP homologous protein (CHOP) cascade, thereby converting an adaptive UPR into a cytotoxic outcome. Functional crosstalk with mitochondrial depolarization and caspase activation further highlights SH003’s ability to exploit ER–mitochondrial stress coupling in redox-vulnerable malignancies.
CHOP activation is widely recognized as a hallmark of ER stress–driven apoptosis [53]. Experimental evidence from preclinical models—including sepsis-induced muscle wasting and renal injury—shows that CHOP induction accelerates maladaptive protein degradation and cell death, whereas CHOP deletion or pathway inhibition alleviates these pathological consequences [54,55]. Clinically, CHOP has been investigated as a biomarker of ER stress in metabolic conditions such as gestational diabetes mellitus [56]. Taken together, these findings suggest that CHOP upregulation could serve as a dynamic and clinically relevant biomarker of ER stress engagement in SH003-treated cancers, warranting further validation in patient-derived cohorts.

2.5. Mitochondrial ROS Disruption

Mitochondria function both as major sources of reactive oxygen species (ROS) and as central regulators of intrinsic apoptosis [57]. SH003-derived phytochemicals, including luteolin and baicalein, perturb mitochondrial homeostasis by suppressing fusion proteins, inducing Bcl-2–associated X protein (BAX)/BAK oligomerization, promoting cytochrome c release, and activating caspases [58]. Through selective disruption of mitochondria with impaired antioxidant defenses, SH003 acts as a targeted mitochondrial redox disruptor. From a pharmacodynamic standpoint, components of the mitochondrial thioredoxin system (Trx/TrxR) constitute core antioxidant circuitry and plausible readouts of oxidative-stress engagement; notably, Trx/TrxR operate alongside SOD/GPX defenses in mitochondria and are functionally coupled to SIRT3-dependent redox control [59,60]. Markers of mitochondrial dysfunction—particularly changes in thioredoxin 2 (TRX2)—have been identified as sensitive indicators of oxidative imbalance. Because TRX2 is critical for mitochondrial ROS detoxification and regulation of apoptosis, its modulation offers both mechanistic insight and a potential pharmacodynamic endpoint for clinical monitoring. Inhibition of the thioredoxin system has been shown to drive ROS accumulation, lipid peroxidation, and either ferroptotic or apoptotic cell death, while early-phase clinical evaluation of TRX inhibitors such as PX-12 reported acceptable safety and tolerability in patients with advanced solid tumors [61]. Collectively, these findings support the translational utility of TRX2 modulation as a biomarker to guide patient stratification and therapeutic response assessment in SH003-based oncology strategies.

2.6. ROS-Generation Properties of SH003 Constituents

The pro-oxidant activity of SH003 arises from the inherent redox characteristics of its phytochemical components. Luteolin acts as a strong ROS generator through catechol-driven redox cycling [62], whereas baicalein produces more moderate ROS elevation by disrupting mitochondrial stability and enhancing endoplasmic reticulum (ER) stress. Even constituents present at lower abundance, such as cucurbitacin D, contribute synergistically by weakening intrinsic antioxidant defenses. Together, these phytochemicals enable SH003 to operate as a network-level modulator of ROS rather than a simple additive effect of single compounds [63,64]. This integrated mode of redox regulation represents a pharmacological mechanism distinct from conventional single-target approaches and highlights the translational potential of multi-component herbal formulations in oncology [65,66]. A comparative summary of constituent-specific functions—including chelation capacity, biomarker relevance, ROS modulation, and anticancer mechanisms—is provided in Table 1.

2.7. Integrated Perspective

From a systems biology standpoint, SH003 is best conceptualized not as a simple aggregation of individual phytochemicals but as a multi-dimensional modulator of redox networks. By simultaneously engaging apoptotic, ferroptotic, and autophagic programs, SH003 illustrates a prototypical approach for counteracting tumor plasticity and drug resistance. Pharmacologically, this integrated mode of action positions SH003 as a systems-level therapeutic strategy, capable of targeting diverse redox-dependent vulnerabilities in cancer.

2.8. Biomarkers and Translational Perspectives

Mechanism-linked biomarker development is fundamental to realizing the translational potential of SH003 [78]. Low GPX4 expression identifies tumors vulnerable to ferroptosis [79], while NRF2 hyperactivation may serve as a predictor of benefit from redox-targeting strategies [80]. CHOP induction reflects engagement of ER stress pathways, and alterations in thioredoxin 2 (TRX2) indicate mitochondrial redox imbalance [81]. While CHOP has shown clinical associations—ranging from serum detectability in critical-illness cohorts to predictive value for chemotherapy outcomes in breast cancer—its oncology-specific use as a pharmacodynamic biomarker for SH003 remains to be prospectively validated, and would benefit from integration with ER-stress readouts and adaptive UPR dynamics in early-phase trials [82,83,84]. As a preclinical corollary, the PERK–ATF4–CHOP axis functions as a gatekeeper of drug/TNFα-induced hepatocyte apoptosis in hepatotoxicity models, reinforcing CHOP’s utility as an ER-stress pharmacodynamic readout [85]. Collectively, these biomarkers offer a framework for patient stratification and dynamic pharmacodynamic monitoring in SH003-based oncology regimens [86]. Clinically, Phase I studies demonstrated safety at doses up to 9600 mg/day without dose-limiting toxicities, whereas combination trials with docetaxel established a maximum tolerated dose of 4800 mg/day. Incorporating biomarker analysis into such trials could support precision-guided application and distinguish SH003 from conventional phytomedicines [7]. An integrated model of SH003-mediated redox modulation—spanning ferroptosis, autophagy, and immune remodeling—is depicted in Figure 2, while Table 2 summarize biomarker associations and constituent-specific mechanistic evidence.

3. Discussion and Translational Perspectives

SH003 imposes ferroptotic stress through the combined actions of cucurbitacin D, luteolin, and baicalein, which synergistically enhance lipid peroxidation and suppress GPX4 activity [90]. This polypharmacological pressure differentiates SH003 from conventional single-pathway inducers and offers a strategy to overcome ferroptosis resistance in redox-adapted tumors. Ferroptosis, an iron-dependent form of regulated cell death characterized by GSH depletion, GPX4 inactivation, and lipid peroxide accumulation, has emerged as a promising anticancer strategy. Yet, clinical translation has been hindered by tumor redox plasticity, iron homeostasis complexity, and concerns about off-target oxidative injury [30,31].
Mechanistic studies illustrate this duality: genetic GPX4 ablation results in embryonic lethality with tissue-specific ferroptosis [30], whereas inhibition of glutathione S-transferase alpha 4 sensitizes macrophages and prevents colorectal tumorigenesis [31]. These findings underscore ferroptosis as both a cell-death pathway and an immunoregulatory mechanism. Recent advances reveal that SH003 constituents intricately modulate iron homeostasis, thereby influencing ferroptotic vulnerability in tumor cells. Luteolin forms stable Fe2+ and Fe3+ chelates through its catechol (3′,4′-dihydroxy) and 5-hydroxy-4-keto coordination sites, which effectively sequester labile iron and suppress Fenton reaction–driven hydroxyl radical generation [91]. This chelating property contributes to reduced lipid peroxidation and preserves membrane integrity under oxidative stress. Baicalein, another major SH003 flavone, exhibits dual functionality: it acts as a potent iron chelator via its 6-,7-dihydroxy moieties while also stabilizing mitochondrial iron pools, thereby preventing Fe2+-induced ROS bursts and GPX4 inactivation. In contrast, cucurbitacin D has been reported to enhance ferritinophagy through NCOA4 activation, liberating stored ferritin-bound Fe2+ and amplifying lipid peroxidation, thus promoting ferroptotic stress in resistant cancer cells. This balanced regulation of iron sequestration (via luteolin and baicalein) and iron release (via cucurbitacin D) suggests that SH003 may achieve a homeostatic ferroptotic threshold—sensitizing tumors to redox imbalance while minimizing systemic oxidative toxicity. Mechanistically, ferroptosis is driven by iron-dependent lipid peroxidation and GPX4 depletion, but recent studies highlight that perturbation of the labile iron pool, ferritinophagy, and mitochondrial Fe2+ overload are decisive in dictating ferroptotic sensitivity [92]. Therefore, integrating iron-handling biomarkers such as ferritin heavy chain (FTH1), ferritin light chain (FTL), transferrin receptor 1 (TFRC), and ferroportin (SLC40A1) into SH003-based studies could clarify its dual iron-chelating and ferroptosis-sensitizing effects, offering a more structured and translationally relevant mechanistic backbone. In this context, SH003’s advancement to Phase I trials (NCT03081819, KCT0004770) underscores its rare translational trajectory as a GMP-standardized multi-herbal formulation [93]. By bridging phytochemistry, pharmacology, and oncology—exemplified by recent studies on the ROS–miRNA–exosome axis [16]—SH003 provides a framework for integrating complex phytomedicines into precision cancer therapy.
Mechanistic alignment with tumor vulnerabilities—including redox addiction, ferroptosis resistance, and immune evasion—supports its relevance for triple-negative breast cancer (TNBC) and EGFR-mutant NSCLC [94,95]. Biomarker-defined subgroups, such as tumors with low GPX4, NRF2 hyperactivation [96], or elevated CHOP/TRX2 [97], may be particularly responsive to SH003-driven stress responses [47,98]. Combination strategies further expand clinical potential: SH003 can enhance PD-L1 suppression and restore T-cell cytotoxicity when combined with Immune Checkpoint Inhibitors (ICIs) [6,99], amplify lipid peroxidation when paired with ferroptosis sensitizers [24,100,101], and has already shown synergy with docetaxel in overcoming resistance while mitigating systemic toxicity [102,103,104]. Although exosome remodeling by SH003 has been supported by metabolomics, its downstream immune consequences warrant validation [105]. In NSCLC models, SH003 ± docetaxel suppresses the EGFR–JAK–STAT3 axis and yields synergistic antitumor activity; accordingly, exosome-based metabolomic signatures in this setting are best positioned as exploratory predictive biomarkers rather than mechanistic effectors, pending prospective immune-functional validation [6,99,102,103,104,105]. Recent mechanistic studies have demonstrated that SH003 and its constituents inhibit the JAK/STAT pathway through both direct and indirect mechanisms. Formononetin and cucurbitacin D suppress JAK2 and STAT3 Tyr705 phosphorylation, hinder STAT3 dimerization and nuclear translocation, and consequently decrease PD-L1 expression and downstream oncogenic targets such as c-Myc and Bcl-xL [106,107]. In parallel, SH003 mitigates ROS-NF-κB–IL-6 signaling, thereby reducing cytokine-driven STAT3 activation and remodeling exosomal cargo, including PD-L1 and immunoregulatory miRNAs (miR-21, miR-155) [107,108]. This dual-level inhibition links redox regulation to immune reactivation, enhancing M1 macrophage polarization and CD8+ T-cell activity while counteracting NRF2-dependent antioxidant and immunosuppressive pathways [107].
In parallel, redox-sensitive miRNAs (miR-200c, miR-96, miR-21, miR-210) are recognized as biomarkers of prognosis, resistance, and immune modulation across cancers [21,31,109,110,111], and their integration into SH003-based interventions could enable biomarker-guided oncology [112].
Beyond exosomal signaling, SH003 may regulate NRF2 stability via GSK3β, providing a KEAP1-independent layer of redox control. This dual regulation highlights SH003’s capacity to destabilize redox adaptation in NRF2-hyperactivated tumors, reinforcing the rationale for biomarker-driven stratification [28,29]. Embedding assays such as GPX4, NRF2, CHOP, and TRX2 into clinical trials will be critical for distinguishing SH003 from conventional phytomedicines.
Most breast cancer trials focus on supportive endpoints—radiodermatitis prevention, perioperative anxiety relief, or menopausal symptom control [113,114]. In contrast, lung cancer studies increasingly explore disease-modifying effects [115,116], including tumor suppression, resistance reversal, and immune modulation [117,118]. This contrast underscores SH003’s unique positioning: unlike supportive agents, SH003 directly enforces ferroptotic pressure, destabilizes NRF2-driven adaptation, and remodels immune–exosome networks.
Conventional chemotherapy (taxanes, platinum-based agents), EGFR-tyrosine kinase inhibitors (TKIs) [116], and ICIs have improved outcomes in breast [119] and lung cancer but remain constrained by toxicities [120], acquired resistance, and immune-related adverse events (irAEs) [115]. Recent herbal interventions have sought to mitigate these issues—for example, alleviating radiodermatitis in breast cancer [114,121], reducing chemotherapy-induced gastrointestinal toxicities in NSCLC [117,118], or improving QoL with immune modulation. Yet, most remain supportive rather than disease-modifying. In contrast, SH003 integrates cytotoxic, ferroptotic, and immunoregulatory mechanisms with favorable safety in Phase I trials, positioning it as a forward-looking phytomedicine capable of synergistic integration into precision oncology. This positioning is further contextualized by Table 3, where most natural product interventions remain supportive rather than disease-modifying. By contrast, SH003—mechanistically anchored and clinically advancing—illustrates how phytomedicine can evolve into a truly disease-modifying oncology therapeutic.

Limitations and Future Directions

SH003-induced exosome remodeling and miRNA-mediated immune regulation are based on indirect or constituent-level studies, necessitating SH003-specific functional validation. In addition, critical aspects of iron–sulfur cluster balance, cancer stem cell metabolic dependencies, and nutrient-stress-conditioned ferroptotic switching remain unresolved. Clinically, available data are restricted to Phase I trials, which confirm safety but do not establish efficacy. Finally, as a multi-component phytomedicine, the precise contribution of individual constituents to overall therapeutic effects have yet to be delineated. Addressing these limitations will require multi-omics integration, spatial transcriptomics, and biomarker-embedded clinical studies to ensure SH003 advances from a supportive adjunct to a precision-guided therapeutic. To operationalize this agenda, we propose an exploratory clinical framework emphasizing KEAP1/NFE2L2-based stratification, NRF2 target-gene signatures, GPX4/PD-L1 status, and correlative pharmacodynamic readouts (including CHOP and the thioredoxin/thioredoxin-reductase system such as TRX2), with exosomal miRNA and metabolomic signatures positioned as exploratory predictive biomarkers, as summarized in Table 4. Future research should exploit the convergence of ferroptosis and immunotherapy. Nanoparticle-based delivery systems could optimize SH003 dosing and tumor targeting, while combinatorial approaches with CAR-T cells, PD-1/PD-L1 blockade, or STING agonists may potentiate cytotoxic T-cell activity and overcome microenvironmental resistance. Such multimodal strategies can advance SH003 from an adjunctive formulation toward a precision-guided therapeutic platform.

4. Conclusions

SH003 exemplifies how a GMP-standardized multi-herbal formulation can progress from mechanistic discovery to clinical translation. By modulating ferroptosis, NRF2 adaptation, and line immune remodeling through STAT3/PD-L1 suppression, SH003 functions as a multi-node redox–immune modulator. These convergent mechanisms provide a foundation for biomarker-informed patient stratification, particularly in GPX4-low or NRF2-hyperactivated tumors. Future clinical studies integrating predictive biomarkers such as GPX4, NRF2, CHOP, TRX2, and exosomal miRNAs will be crucial to validate SH003 as a prototype phytomedicine for precision oncology.

Author Contributions

M.N.P.: Conceptualization, Resources; Investigation; Funding acquisition; Visualization; Writing—original draft; Writing—review and editing; Supervision. M.M.H.F.: Software; Visualization; Data curation; Methodology; Formal analysis; Writing—original draft; Writing—review and editing. H.N.K.: Visualization; Formal analysis; Writing—original draft; Writing—review and editing. H.B.: Data curation; Writing—original draft; Writing—review and editing. A.R.: Writing—original draft; Writing—review and editing. F.N.: Methodology; Writing—original draft; Writing—review and editing. T.E.T.: Writing—original draft; Writing—review and editing. S.-G.K.: Writing—review; Writing—review and editing. B.K.: Conceptualization; Validation; Writing—review; Writing—review and editing; Project administration; Supervision. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the following grants: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1I1A2066868), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2020-NR049559), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2020-KH087790), the Starting Growth Technological R&D Program (TIPS Program, No. RS-2024-00507224) funded by the Ministry of SMEs and Startups (MSS, Korea) in 2024, and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2024-00350362), and grants from the National Research Foundation of Korea (grant numbers: 2021R1C1C2014229).

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
4-HNE4-hydroxynonenal
ACSL4acyl-CoA synthetase long chain family member 4
AKTprotein kinase B
AMPKAMP-activated protein kinase
ATF4activating transcription factor 4
BAK1BCL2 antagonist/killer 1
BAXBCL2-associated X apoptosis regulator
CHOPDNA damage inducible transcript 3
CYCScytochrome c, somatic
eIF2αeukaryotic translation initiation factor 2 subunit alpha
ERendoplasmic reticulum
GPX4glutathione peroxidase 4
GSK3βglycogen synthase kinase 3 beta
HO-1heme oxygenase 1
JAK2Janus kinase 2
KEAP1kelch-like ECH-associated protein 1
LPCAT3lysophosphatidylcholine acyltransferase 3
miRNAmicroRNA
NF-κBnuclear factor kappa B
NQO1NAD(P)H quinone dehydrogenase 1
NRF2NFE2-like bZIP transcription factor 2
NSCLCnon-small cell lung cancer
OXPHOSoxidative phosphorylation
p62/SQSTM1sequestosome 1
PD-L1Programmed death-ligand 1
PERKeukaryotic translation initiation factor 2 alpha kinase 3
PI3Kphosphatidylinositol 3-kinase
ROSreactive oxygen species
SLC7A11solute carrier family 7 member 11
STAT3signal transducer and activator of transcription 3
TNBCtriple-negative breast cancer
Tregregulatory T cell
TRX2thioredoxin 2
ULK1Unc-51 like autophagy activating kinase 1
UPRunfolded protein response
VPS34class III phosphatidylinositol 3-kinase (PIK3C3)

References

  1. Ju, S.; Singh, M.K.; Han, S.; Ranbhise, J.; Ha, J.; Choe, W.; Yoon, K.S.; Yeo, S.G.; Kim, S.S.; Kang, I. Oxidative Stress and Cancer Therapy: Controlling Cancer Cells Using Reactive Oxygen Species. Int. J. Mol. Sci. 2024, 25, 12387. [Google Scholar] [CrossRef]
  2. Hayashi, M.; Okazaki, K.; Papgiannakopoulos, T.; Motohashi, H. The Complex Roles of Redox and Antioxidant Biology in Cancer. Cold Spring Harb. Perspect. Med. 2024, 14, a041546. [Google Scholar] [CrossRef]
  3. Choi, Y.K.; Cho, S.G.; Woo, S.M.; Yun, Y.J.; Park, S.; Shin, Y.C.; Ko, S.G. Herbal extract SH003 suppresses tumor growth and metastasis of MDA-MB-231 breast cancer cells by inhibiting STAT3-IL-6 signaling. Mediat. Inflamm. 2014, 2014, 492173. [Google Scholar] [CrossRef]
  4. Kim, H.J.; Lee, J.Y.; Cheon, C.; Ko, S.-G. Development and Validation of a New Analytical HPLC-PDA Method for Simultaneous Determination of Cucurbitacins B and D from the Roots of Trichosanthes kirilowii. J. Chem. 2022, 2022, 2109502. [Google Scholar] [CrossRef]
  5. Kim, H.I.; Han, Y.; Kim, M.H.; Boo, M.; Cho, K.J.; Kim, H.L.; Lee, I.S.; Jung, J.H.; Kim, W.; Um, J.Y.; et al. The multi-herbal decoction SH003 alleviates LPS-induced acute lung injury by targeting inflammasome and extracellular traps in neutrophils. Phytomedicine 2024, 133, 155926. [Google Scholar] [CrossRef] [PubMed]
  6. Choi, Y.-J.; Lee, S.-E.; Kim, D.; Lim, H.-I.; Choi, D.K.; Park, B.K.; Jeon, C.-Y.; Ko, S.-G. The combination of SH003 and DTX induces cytotoxic cell infiltration in anti-PD1 resistant lung cancer. Cancer Immunol. Immunother. 2025, 74, 198. [Google Scholar] [CrossRef] [PubMed]
  7. Cheon, C.; Lee, H.W.; Sym, S.J.; Ko, S.-G. Safety of the herbal medicine SH003 in patients with solid cancer: A multi-center, single-arm, open-label, dose-escalation phase I study. Integr. Cancer Ther. 2024, 23, 15347354241293451. [Google Scholar] [CrossRef]
  8. Cheon, C.; Ko, S.-G. A phase I study to evaluate the safety of the herbal medicine SH003 in patients with solid cancer. Integr. Cancer Ther. 2020, 19, 1534735420911442. [Google Scholar] [CrossRef] [PubMed]
  9. Cheon, C.; Kim, H.; Kang, S.Y.; Lee, S.Y.; Park, K.H.; Ko, S.-G. Safety Evaluation of SH003 and Docetaxel Combination in Patients With Breast and Lung Cancer: A Multi-Center, Open-Label, Dose Escalation Phase I Clinical Trial. Integr. Cancer Ther. 2025, 24, 15347354251363892. [Google Scholar] [CrossRef]
  10. Luo, L.-Y.; Fan, M.-X.; Zhao, H.-Y.; Li, M.-X.; Wu, X.; Gao, W.-Y. Pharmacokinetics and bioavailability of the isoflavones formononetin and ononin and their in vitro absorption in ussing chamber and Caco-2 cell models. J. Agric. Food Chem. 2018, 66, 2917–2924, Correction in: J. Agric. Food Chem. 2018, 66, 12453. [Google Scholar] [CrossRef]
  11. Jia, X.; Chen, J.; Lin, H.; Hu, M. Disposition of flavonoids via enteric recycling: Enzyme-transporter coupling affects metabolism of biochanin A and formononetin and excretion of their phase II conjugates. J. Pharmacol. Exp. Ther. 2004, 310, 1103–1113. [Google Scholar] [CrossRef]
  12. Ding, M.; Bao, Y.; Liang, H.; Zhang, X.; Li, B.; Yang, R.; Zeng, N. Potential mechanisms of formononetin against inflammation and oxidative stress: A review. Front. Pharmacol. 2024, 15, 1368765. [Google Scholar] [CrossRef]
  13. Urabe, F.; Kosaka, N.; Ito, K.; Kimura, T.; Egawa, S.; Ochiya, T. Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am. J. Physiol. Cell Physiol. 2020, 318, C29–C39. [Google Scholar] [CrossRef]
  14. Xiong, Y.; Xiong, Y.; Zhang, H.; Zhao, Y.; Han, K.; Zhang, J.; Zhao, D.; Yu, Z.; Geng, Z.; Wang, L.; et al. hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4(+) T Cells by Targeting the PTEN/PI3K-Nrf2 Axis. Front. Immunol. 2021, 12, 780897. [Google Scholar] [CrossRef]
  15. Wang, M.; Sun, Y.; Yuan, D.; Yue, S.; Yang, Z. Follicular fluid derived exosomal miR-4449 regulates cell proliferation and oxidative stress by targeting KEAP1 in human granulosa cell lines KGN and COV434. Exp. Cell Res. 2023, 430, 113735. [Google Scholar] [CrossRef]
  16. Park, M.N.; Kim, M.; Lee, S.; Kang, S.; Ahn, C.-H.; Tallei, T.E.; Kim, W.; Kim, B. Targeting Redox Signaling Through Exosomal MicroRNA: Insights into Tumor Microenvironment and Precision Oncology. Antioxidants 2025, 14, 501. [Google Scholar] [CrossRef] [PubMed]
  17. Lei, D.; Li, B.; Isa, Z.; Ma, X.; Zhang, B. Hypoxia-elicited cardiac microvascular endothelial cell-derived exosomal miR-210–3p alleviate hypoxia/reoxygenation-induced myocardial cell injury through inhibiting transferrin receptor 1-mediated ferroptosis. Tissue Cell 2022, 79, 101956. [Google Scholar] [CrossRef]
  18. Nitti, M.; Marengo, B.; Furfaro, A.L.; Pronzato, M.A.; Marinari, U.M.; Domenicotti, C.; Traverso, N. Hormesis and oxidative distress: Pathophysiology of reactive oxygen species and the open question of antioxidant modulation and supplementation. Antioxidants 2022, 11, 1613. [Google Scholar] [CrossRef]
  19. Xu, L.; Cao, Y.; Xu, Y.; Li, R.; Xu, X. Redox-Responsive Polymeric Nanoparticle for Nucleic Acid Delivery and Cancer Therapy: Progress, Opportunities, and Challenges. Macromol. Biosci. 2024, 24, 2300238. [Google Scholar] [CrossRef] [PubMed]
  20. Hu, C.; Meiners, S.; Lukas, C.; Stathopoulos, G.T.; Chen, J. Role of exosomal microRNAs in lung cancer biology and clinical applications. Cell Prolif. 2020, 53, e12828. [Google Scholar] [CrossRef] [PubMed]
  21. Masaoutis, C.; Mihailidou, C.; Tsourouflis, G.; Theocharis, S. Exosomes in lung cancer diagnosis and treatment. From the translating research into future clinical practice. Biochimie 2018, 151, 27–36. [Google Scholar] [CrossRef]
  22. Vautrot, V.; Chanteloup, G.; Elmallah, M.; Cordonnier, M.; Aubin, F.; Garrido, C.; Gobbo, J. Exosomal miRNA: Small Molecules, Big Impact in Colorectal Cancer. J. Oncol. 2019, 2019, 8585276. [Google Scholar] [CrossRef] [PubMed]
  23. Petroušková, P.; Hudáková, N.; Maloveská, M.; Humeník, F.; Cizkova, D. Non-Exosomal and Exosome-Derived miRNAs as Promising Biomarkers in Canine Mammary Cancer. Life 2022, 12, 524. [Google Scholar] [CrossRef] [PubMed]
  24. Bi, R.; Hu, R.; Jiang, L.; Wen, B.; Jiang, Z.; Liu, H.; Mei, J. Butyrate enhances erastin-induced ferroptosis of lung cancer cells via modulating the ATF3/SLC7A11 pathway. Environ. Toxicol. 2024, 39, 529–538. [Google Scholar] [CrossRef] [PubMed]
  25. Zhu, Q.; Zhang, K.; Cao, Y.; Hu, Y. Adipose stem cell exosomes, stimulated by pro-inflammatory factors, enhance immune evasion in triple-negative breast cancer by modulating the HDAC6/STAT3/PD-L1 pathway through the transporter UCHL1. Cancer Cell Int. 2024, 24, 385. [Google Scholar] [CrossRef]
  26. Jeong, M.-S.; Lee, K.-W.; Choi, Y.-J.; Kim, Y.-G.; Hwang, H.-H.; Lee, S.-Y.; Jung, S.-E.; Park, S.-A.; Lee, J.-H.; Joo, Y.-J. Synergistic antitumor activity of SH003 and docetaxel via EGFR signaling inhibition in non-small cell lung cancer. Int. J. Mol. Sci. 2021, 22, 8405. [Google Scholar] [CrossRef]
  27. Cheon, C.; Ko, S.-G. Phase I study to evaluate the maximum tolerated dose of the combination of SH003 and docetaxel in patients with solid cancer: A study protocol. Medicine 2020, 99, e22228. [Google Scholar] [CrossRef]
  28. Choi, H.S.; Ku, J.K.; Ko, S.G.; Yun, P.Y. Anticancer effects of SH003 and its active component Cucurbitacin D on oral cancer cell lines via modulation of EMT and cell viability. Oncol. Res. 2025, 33, 1217–1227. [Google Scholar] [CrossRef]
  29. Han, N.R.; Kim, K.C.; Kim, J.S.; Ko, S.G.; Park, H.J.; Moon, P.D. The immune-enhancing effects of a mixture of Astragalus membranaceus (Fisch.) Bunge, Angelica gigas Nakai, and Trichosanthes Kirilowii (Maxim.) or its active constituent nodakenin. J. Ethnopharmacol. 2022, 285, 114893. [Google Scholar] [CrossRef]
  30. He, W.; Chang, L.; Li, X.; Mei, Y. Research progress on the mechanism of ferroptosis and its role in diabetic retinopathy. Front. Endocrinol. 2023, 14, 1155296. [Google Scholar] [CrossRef]
  31. Ju, Y.; Ma, C.; Huang, L.; Tao, Y.; Li, T.; Li, H.; Huycke, M.M.; Yang, Y.; Wang, X. Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis. Gut Microbes 2025, 17, 2451090. [Google Scholar] [CrossRef]
  32. Yang, M.; Chen, X.; Cheng, C.; Yan, W.; Guo, R.; Wang, Y.; Zhang, H.; Chai, J.; Cheng, Y.; Zhang, F. Cucurbitacin B induces ferroptosis in oral leukoplakia via the SLC7A11/mitochondrial oxidative stress pathway. Phytomedicine 2024, 129, 155548. [Google Scholar] [CrossRef]
  33. Li, H.; Li, J.-X.; Zeng, Y.-D.; Zheng, C.-X.; Dai, S.-S.; Yi, J.; Song, X.-D.; Liu, T.; Liu, W.-H. Luteolin ameliorates ischemic/reperfusion injury by inhibiting ferroptosis. Metab. Brain Dis. 2025, 40, 159. [Google Scholar] [CrossRef] [PubMed]
  34. Li, H.; Qiu, Z.; Chen, L.; Zhang, T.; Wei, D.; Chen, X.; Wang, Y. Cadmium Inhibits Proliferation of Human Bronchial Epithelial BEAS-2B Cells Through Inducing Ferroptosis via Targeted Regulation of the Nrf2/SLC7A11/GPX4 Pathway. Int. J. Mol. Sci. 2025, 26, 7204. [Google Scholar] [CrossRef]
  35. Tang, R.; Zhang, L.; Lou, J.; Mo, W.; Zhao, L.; Li, L.; Zhang, K.; Yu, Q. Formononetin prevents intestinal injury caused by radiotherapy in colorectal cancer mice via the Keap1-Nrf2 signaling pathway. Biochem. Biophys. Res. Commun. 2025, 761, 151676. [Google Scholar] [CrossRef] [PubMed]
  36. Ambrose, G.O.; Afees, O.J.; Nwamaka, N.C.; Simon, N.; Oluwaseun, A.A.; Soyinka, T.; Oluwaseun, A.S.; Bankole, S. Selection of Luteolin as a potential antagonist from molecular docking analysis of EGFR mutant. Bioinformation 2018, 14, 241–247. [Google Scholar] [CrossRef] [PubMed]
  37. Dong, X.; Liu, X.; Lin, D.; Zhang, L.; Wu, Y.; Chang, Y.; Jin, M.; Huang, G. Baicalin induces cell death of non-small cell lung cancer cells via MCOLN3-mediated lysosomal dysfunction and autophagy blockage. Phytomedicine 2024, 133, 155872. [Google Scholar] [CrossRef]
  38. Sahu, P.K.; Sahu, R.; Mishra, D.P.; Padmaja, K.; Mishra, S.K. Leea macrophylla root extract possess potential cytotoxicity in vitro against HepG2, MCF7 cells and in vivo in EAC xenografted model. Adv. Tradit. Med. 2025, 1–21. [Google Scholar] [CrossRef]
  39. Mann, G.E.; Bonacasa, B.; Ishii, T.; Siow, R.C. Targeting the redox sensitive Nrf2-Keap1 defense pathway in cardiovascular disease: Protection afforded by dietary isoflavones. Curr. Opin. Pharmacol. 2009, 9, 139–145. [Google Scholar] [CrossRef]
  40. Dastghaib, S.; Shafiee, S.M.; Ramezani, F.; Ashtari, N.; Tabasi, F.; Saffari-Chaleshtori, J.; Vakili, O.; Siri, M.; Igder, S.; Zamani, M.; et al. NRF1 or NRF2: Emerging Role of Redox Homeostasis on PERK/NRF/Autophagy Mediated Antioxidant in Tumor and Patient Dependent Chemo Sensitivity. Preprints 2024, 2024010079. [Google Scholar] [CrossRef]
  41. Wang, X.; Kang, N.; Liu, Y.; Xu, G. Formononetin Exerts Neuroprotection in Parkinson’s Disease via the Activation of the Nrf2 Signaling Pathway. Molecules 2024, 29, 5364. [Google Scholar] [CrossRef]
  42. Chen, H.; Lou, Y.; Lin, S.; Tan, X.; Zheng, Y.; Yu, H.; Jiang, R.; Wei, Y.; Huang, H.; Qi, X.; et al. Formononetin, a bioactive isoflavonoid constituent from Astragalus membranaceus (Fisch.) Bunge, ameliorates type 1 diabetes mellitus via activation of Keap1/Nrf2 signaling pathway: An integrated study supported by network pharmacology and experimental validation. J. Ethnopharmacol. 2024, 322, 117576. [Google Scholar] [CrossRef] [PubMed]
  43. Sugimoto, M.; Ko, R.; Goshima, H.; Koike, A.; Shibano, M.; Fujimori, K. Formononetin attenuates H2O2-induced cell death through decreasing ROS level by PI3K/Akt-Nrf2-activated antioxidant gene expression and suppressing MAPK-regulated apoptosis in neuronal SH-SY5Y cells. NeuroToxicology 2021, 85, 186–200. [Google Scholar] [CrossRef]
  44. Xu, K.; Ma, J.; Hall, S.R.; Peng, R.-W.; Yang, H.; Yao, F. Battles against aberrant KEAP1-NRF2 signaling in lung cancer: Intertwined metabolic and immune networks. Theranostics 2023, 13, 704. [Google Scholar] [CrossRef]
  45. MacLeod, A.K.; Acosta-Jimenez, L.; Coates, P.J.; McMahon, M.; Carey, F.A.; Honda, T.; Henderson, C.J.; Wolf, C.R. Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer. Br. J. Cancer 2016, 115, 1530–1539. [Google Scholar] [CrossRef]
  46. Pillai, R.; Hayashi, M.; Zavitsanou, A.-M.; Papagiannakopoulos, T. NRF2: KEAPing tumors protected. Cancer Discov. 2022, 12, 625–643. [Google Scholar] [CrossRef]
  47. Zavitsanou, A.-M.; Pillai, R.; Hao, Y.; Wu, W.L.; Bartnicki, E.; Karakousi, T.; Rajalingam, S.; Herrera, A.; Karatza, A.; Rashidfarrokhi, A. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. Cell Rep. 2023, 42, 113295. [Google Scholar] [CrossRef] [PubMed]
  48. Wu, C.-F.; Lee, M.-G.; El-Shazly, M.; Lai, K.-H.; Ke, S.-C.; Su, C.-W.; Shih, S.-P.; Sung, P.-J.; Hong, M.-C.; Wen, Z.-H. Isoaaptamine induces T-47D cells apoptosis and autophagy via oxidative stress. Mar. Drugs 2018, 16, 18. [Google Scholar] [CrossRef]
  49. Miao, X.; Zhuang, Z.; Zhou, Y.; Zhou, Y.; Xu, J.; Liu, Y. Serum SQSTM1 is a potential predictor for chemotherapeutic efficacy against non-small cell lung cancer. Int. J. Clin. Exp. Med. 2018, 11, 5811–5819. [Google Scholar]
  50. Hsu, H.Y.; Lin, T.Y.; Lu, M.K.; Leng, P.J.; Tsao, S.M.; Wu, Y.C. Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer. Sci. Rep. 2017, 7, 44990. [Google Scholar] [CrossRef] [PubMed]
  51. Chaudhary, P.; Janmeda, P.; Pareek, A.; Chuturgoon, A.A.; Sharma, R.; Pareek, A. Etiology of lung carcinoma and treatment through medicinal plants, marine plants and green synthesized nanoparticles: A comprehensive review. Biomed. Pharmacother. 2024, 173, 116294. [Google Scholar] [CrossRef] [PubMed]
  52. Kim, J.; Yun, M.; Kim, E.O.; Jung, D.B.; Won, G.; Kim, B.; Jung, J.H.; Kim, S.H. Decursin enhances TRAIL-induced apoptosis through oxidative stress mediated- endoplasmic reticulum stress signalling in non-small cell lung cancers. Br. J. Pharmacol. 2016, 173, 1033–1044. [Google Scholar] [CrossRef]
  53. Zasheva, D.; Mladenov, P.; Rusanov, K.; Simova, S.; Zapryanova, S.; Simova-Stoilova, L.; Moyankova, D.; Djilianov, D. Fractions of Methanol Extracts from the Resurrection Plant Haberlea rhodopensis Have Anti-Breast Cancer Effects in Model Cell Systems. Separations 2023, 10, 388. [Google Scholar] [CrossRef]
  54. Zheng, Y.; Dai, H.; Chen, R.; Zhong, Y.; Zhou, C.; Wang, Y.; Zhan, C.; Luo, J. Endoplasmic reticulum stress promotes sepsis-induced muscle atrophy via activation of STAT3 and Smad3. J. Cell. Physiol. 2023, 238, 582–596. [Google Scholar] [CrossRef]
  55. Ricciardi, C.A.; Gnudi, L. The endoplasmic reticulum stress and the unfolded protein response in kidney disease: Implications for vascular growth factors. J. Cell. Mol. Med. 2020, 24, 12910–12919. [Google Scholar] [CrossRef]
  56. Sarıkaya, S.; Almaghrebi, E.; Akat, F.; Hepbildi, E.N.; Kosucu, E.; Körez, M.K.; Vatansev, H. Investigation of endoplasmic reticulum stress parameters in patients with gestational diabetes mellitus: A prospective study. Int. J. Gynaecol. Obstet. 2025, 170, 774–782. [Google Scholar] [CrossRef] [PubMed]
  57. Chen, D.; Shen, F.; Liu, J.; Tang, H.; Zhang, K.; Teng, X.; Yang, F. The protective effect of Luteolin on chicken spleen lymphocytes from ammonia poisoning through mitochondria and balancing energy metabolism disorders. Poult. Sci. 2023, 102, 103093. [Google Scholar] [CrossRef] [PubMed]
  58. Atlante, A.; Calissano, P.; Bobba, A.; Azzariti, A.; Marra, E.; Passarella, S. Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death. J. Biol. Chem. 2000, 275, 37159–37166. [Google Scholar] [CrossRef]
  59. Yang, J.; Lu, Y.; Zhao, Y.; Wang, X. Mechanisms of SIRT3 regulation of aging and aging-related diseases and advances in drug therapy. Gerontology 2025, 68, 1–16. [Google Scholar] [CrossRef]
  60. Bhullar, K.S.; Rupasinghe, H.V. Polyphenols: Multipotent therapeutic agents in neurodegenerative diseases. Oxidative Med. Cell. Longev. 2013, 2013, 891748. [Google Scholar] [CrossRef]
  61. Song, T.; Yu, Z.; Shen, Q.; Xu, Y.; Hu, H.; Liu, J.; Zeng, K.; Lei, J.; Yu, L. Pharmacodynamic and Toxicity Studies of 6-Isopropyldithio-2′-guanosine Analogs in Acute T-Lymphoblastic Leukemia. Cancers 2024, 16, 1614. [Google Scholar] [CrossRef]
  62. Slika, H.; Mansour, H.; Wehbe, N.; Nasser, S.A.; Iratni, R.; Nasrallah, G.; Shaito, A.; Ghaddar, T.; Kobeissy, F.; Eid, A.H. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed. Pharmacother. 2022, 146, 112442. [Google Scholar] [CrossRef]
  63. Pietta, P.G. Flavonoids as antioxidants. J. Nat. Prod. 2000, 63, 1035–1042. [Google Scholar] [CrossRef]
  64. Procházková, D.; Boušová, I.; Wilhelmová, N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011, 82, 513–523. [Google Scholar] [CrossRef]
  65. Vaidya, T. Multiscale and Translational Quantitative Systems-Based Modeling and Simulation for Efficacy and Safety Assessment of Anti-Cancer Agents. Ph.D. Thesis, University of Florida, Gainesville, FL, USA, 2020. [Google Scholar]
  66. Zhao, M.; Scott, S.; Evans, K.W.; Yuca, E.; Saridogan, T.; Zheng, X.; Wang, H.; Korkut, A.; Cruz Pico, C.X.; Demirhan, M. Combining neratinib with CDK4/6, mTOR, and MEK inhibitors in models of HER2-positive cancer. Clin. Cancer Res. 2021, 27, 1681–1694. [Google Scholar] [CrossRef] [PubMed]
  67. Lai, J.-Q.; Zhao, L.-L.; Hong, C.; Zou, Q.-M.; Su, J.-X.; Li, S.-J.; Zhou, X.-F.; Li, Z.-S.; Deng, B.; Cao, J.; et al. Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis. Acta Pharmacol. Sin. 2024, 45, 1715–1726. [Google Scholar] [CrossRef] [PubMed]
  68. Min, D.Y.; Jung, E.; Ahn, S.S.; Lee, Y.H.; Lim, Y.; Shin, S.Y. Chrysoeriol Prevents TNFα-Induced CYP19 Gene Expression via EGR-1 Downregulation in MCF7 Breast Cancer Cells. Int. J. Mol. Sci. 2020, 21, 7523. [Google Scholar] [CrossRef] [PubMed]
  69. Bakar-Ates, F.; Ozkan, E. Cucurbitacin B and erastin co-treatment synergistically induced ferroptosis in breast cancer cells via altered iron-regulating proteins and lipid peroxidation. Toxicol. In Vitro 2024, 94, 105732. [Google Scholar] [CrossRef]
  70. Huang, S.; Cao, B.; Zhang, J.; Feng, Y.; Wang, L.; Chen, X.; Su, H.; Liao, S.; Liu, J.; Yan, J.; et al. Induction of ferroptosis in human nasopharyngeal cancer cells by cucurbitacin B: Molecular mechanism and therapeutic potential. Cell Death Dis. 2021, 12, 237. [Google Scholar] [CrossRef]
  71. Kim, D.; Go, S.H.; Song, Y.; Lee, D.K.; Park, J.R. Decursin Induces G1 Cell Cycle Arrest and Apoptosis through Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Human Colorectal Cancer Cells in In Vitro and Xenograft Models. Int. J. Mol. Sci. 2024, 25, 9939. [Google Scholar] [CrossRef]
  72. Kim, T.W.; Ko, S.G. The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells. Antioxidants 2021, 10, 1881. [Google Scholar] [CrossRef] [PubMed]
  73. Fang, Y.; Ye, J.; Zhao, B.; Sun, J.; Gu, N.; Chen, X.; Ren, L.; Chen, J.; Cai, X.; Zhang, W.; et al. Formononetin ameliorates oxaliplatin-induced peripheral neuropathy via the KEAP1-NRF2-GSTP1 axis. Redox Biol. 2020, 36, 101677. [Google Scholar] [CrossRef]
  74. Gao, H.; Wang, H.; Peng, J. Hispidulin induces apoptosis through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway in HepG2 cancer cells. Cell Biochem. Biophys. 2014, 69, 27–34. [Google Scholar] [CrossRef]
  75. Lv, L.; Zhang, W.; Li, T.; Jiang, L.; Lu, X.; Lin, J. Hispidulin exhibits potent anticancer activity in vitro and in vivo through activating ER stress in non-small-cell lung cancer cells. Oncol. Rep. 2020, 43, 1995–2003. [Google Scholar] [CrossRef]
  76. Eryilmaz, I.E.; Colakoglu Bergel, C.; Arioz, B.; Huriyet, N.; Cecener, G.; Egeli, U. Luteolin induces oxidative stress and apoptosis via dysregulating the cytoprotective Nrf2-Keap1-Cul3 redox signaling in metastatic castration-resistant prostate cancer cells. Mol. Biol. Rep. 2024, 52, 65. [Google Scholar] [CrossRef]
  77. Cao, Q.; Ding, S.; Zheng, X.; Li, H.; Yu, L.; Zhu, Y.; Jiang, D.; Ruan, S. Luteolin Induces GPX4-dependent Ferroptosis and Enhances Immune Activation in Colon Cancer. Phytomedicine 2025, 146, 157117. [Google Scholar] [CrossRef] [PubMed]
  78. Zhang, W.; Liu, Y.; Liao, Y.; Zhu, C.; Zou, Z. GPX4, ferroptosis, and diseases. Biomed. Pharmacother. 2024, 174, 116512. [Google Scholar] [CrossRef]
  79. Xu, Y.; Tong, Y.; Lei, Z.; Zhu, J.; Wan, L. Abietic acid induces ferroptosis via the activation of the HO-1 pathway in bladder cancer cells. Biomed. Pharmacother. 2023, 158, 114154. [Google Scholar] [CrossRef] [PubMed]
  80. Barrera, G.; Cucci, M.A.; Grattarola, M.; Dianzani, C.; Muzio, G.; Pizzimenti, S. Control of Oxidative Stress in Cancer Chemoresistance: Spotlight on Nrf2 Role. Antioxidants 2021, 10, 510. [Google Scholar] [CrossRef]
  81. Wu, X.; Wang, Q.; Lu, Y.; Zhang, J.; Yin, H.; Yi, Y. Clinical application of thioredoxin reductase as a novel biomarker in liver cancer. Sci. Rep. 2021, 11, 6069. [Google Scholar] [CrossRef]
  82. Li, F.; Lin, Q.; Shen, L.; Zhang, Z.; Wang, P.; Zhang, S.; Xing, Q.; Xia, Z.; Zhao, Z.; Zhang, Y. The diagnostic value of endoplasmic reticulum stress-related specific proteins GRP78 and CHOP in patients with sepsis: A diagnostic cohort study. Ann. Transl. Med. 2022, 10, 470. [Google Scholar] [CrossRef]
  83. Zheng, Y.-Z.; Cao, Z.-G.; Hu, X.; Shao, Z.-M. The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Res. Treat. 2014, 145, 349–358. [Google Scholar] [CrossRef] [PubMed]
  84. Liu, K.; Zhao, C.; Adajar, R.C.; DeZwaan-McCabe, D.; Rutkowski, D.T. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. EMBO Rep. 2024, 25, 228–253. [Google Scholar] [CrossRef] [PubMed]
  85. Fredriksson, L.; Wink, S.; Herpers, B.; Benedetti, G.; Hadi, M.; Bont, H.d.; Groothuis, G.; Luijten, M.; Danen, E.; Graauw, M.d. Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFα-mediated hepatotoxicity. Toxicol. Sci. 2014, 140, 144–159. [Google Scholar] [CrossRef] [PubMed]
  86. Ha, J.-H.; Lee, B.-W.; Yi, D.-H.; Lee, S.-J.; Kim, W.-I.; Pak, S.-W.; Kim, H.-Y.; Kim, S.-H.; Shin, I.-S.; Kim, J.-C.; et al. Particulate matter-mediated oxidative stress induces airway inflammation and pulmonary dysfunction through TXNIP/NF-κB and modulation of the SIRT1-mediated p53 and TGF-β/Smad3 pathways in mice. Food Chem. Toxicol. 2024, 183, 114201. [Google Scholar] [CrossRef]
  87. Hao, Y.; Miao, J.; Liu, W.; Peng, L.; Chen, Y.; Zhong, Q. Formononetin protects against cisplatin-induced acute kidney injury through activation of the PPARα/Nrf2/HO-1/NQO1 pathway. Int. J. Mol. Med. 2021, 47, 511–522. [Google Scholar] [CrossRef]
  88. Jeon, Y.J.; Shin, J.I.; Lee, S.; Lee, Y.G.; Kim, J.B.; Kwon, H.C.; Kim, S.H.; Kim, I.; Lee, K.; Han, Y.S. Angelica gigas Nakai Has Synergetic Effects on Doxorubicin-Induced Apoptosis. Biomed. Res. Int. 2018, 2018, 6716547. [Google Scholar] [CrossRef]
  89. Fathy, N.; Farouk, S.; Sayed, R.H.; Fahim, A.T. Ezetimibe ameliorates cisplatin-induced nephrotoxicity: A novel therapeutic approach via modulating AMPK/Nrf2/TXNIP signaling. FASEB J. 2024, 38, e23382. [Google Scholar] [CrossRef]
  90. Tang, Y.; Zhuang, Y.; Zhao, C.; Gu, S.; Zhang, J.; Bi, S.; Wang, M.; Bao, L.; Li, M.; Zhang, W.; et al. The metabolites from traditional Chinese medicine targeting ferroptosis for cancer therapy. Front. Pharmacol. 2024, 15, 1280779. [Google Scholar] [CrossRef] [PubMed]
  91. Kejík, Z.; Kaplánek, R.; Masařík, M.; Babula, P.; Matkowski, A.; Filipenský, P.; Veselá, K.; Gburek, J.; Sýkora, D.; Martásek, P. Iron complexes of flavonoids-antioxidant capacity and beyond. Int. J. Mol. Sci. 2021, 22, 646. [Google Scholar] [CrossRef]
  92. Tan, R.; Ge, C.; Yan, Y.; Guo, H.; Han, X.; Zhu, Q.; Du, Q. Deciphering ferroptosis in critical care: Mechanisms, consequences, and therapeutic opportunities. Front. Immunol. 2024, 15, 1511015. [Google Scholar] [CrossRef]
  93. Cheon, C.; Kang, S.; Ko, Y.; Kim, M.; Jang, B.H.; Shin, Y.C.; Ko, S.G. Single-arm, open-label, dose-escalation phase I study to evaluate the safety of a herbal medicine SH003 in patients with solid cancer: A study protocol. BMJ Open 2018, 8, e019502. [Google Scholar] [CrossRef]
  94. Atwell, B.; Chalasani, P.; Schroeder, J. Nuclear epidermal growth factor receptor as a therapeutic target. Explor. Target. Antitumor Ther. 2023, 4, 616–629. [Google Scholar] [CrossRef]
  95. Zhou, F.; Guo, H.; Xia, Y.; Le, X.; Tan, D.S.W.; Ramalingam, S.S.; Zhou, C. The changing treatment landscape of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Clin. Oncol. 2025, 22, 95–116. [Google Scholar] [CrossRef]
  96. Choi, Y.K.; Cho, S.-G.; Choi, Y.-J.; Yun, Y.J.; Lee, K.M.; Lee, K.; Yoo, H.-H.; Shin, Y.C.; Ko, S.-G. SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes. Oncotarget 2016, 8, 88386. [Google Scholar] [CrossRef]
  97. Kim, T.W.; Cheon, C.; Ko, S.G. SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells. Cell Death Dis. 2020, 11, 717. [Google Scholar] [CrossRef] [PubMed]
  98. Delgobo, M.; Gonçalves, R.M.; Delazeri, M.A.; Falchetti, M.; Zandoná, A.; Nascimento das Neves, R.; Almeida, K.; Fagundes, A.C.; Gelain, D.P.; Fracasso, J.I.; et al. Thioredoxin reductase-1 levels are associated with NRF2 pathway activation and tumor recurrence in non-small cell lung cancer. Free Radic. Biol. Med. 2021, 177, 58–71. [Google Scholar] [CrossRef] [PubMed]
  99. Han, N.-R.; Park, H.-J.; Ko, S.-G.; Moon, P.-D. The Mixture of Natural Products SH003 Exerts Anti-Melanoma Effects through the Modulation of PD-L1 in B16F10 Cells. Nutrients 2023, 15, 2790. [Google Scholar] [CrossRef]
  100. Wongjaikam, S.; Siengdee, P.; Somnus, A.; Govitrapong, P. Melatonin Alleviates Erastin-Induced Cell Death by Inhibiting Ferroptosis and Amyloid Precursor Protein Processing in Neuronal Cell Lines. Neurotox. Res. 2025, 43, 25. [Google Scholar] [CrossRef] [PubMed]
  101. Abdullah, M.; Lee, S.J. Extracellular Concentration of L-Cystine Determines the Sensitivity to System x(c) (-) Inhibitors. Biomol. Ther. 2022, 30, 184–190. [Google Scholar] [CrossRef]
  102. Lei, H.; Wang, G.; Zhang, J.; Han, Q. Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity. Oncol. Rep. 2018, 40, 3447–3457. [Google Scholar] [CrossRef]
  103. Wigner, P.; Dziedzic, A.; Synowiec, E.; Miller, E.; Bijak, M.; Saluk-Bijak, J. Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: A preliminary study. Sci. Rep. 2022, 12, 10603. [Google Scholar] [CrossRef]
  104. Udler, M.; Maia, A.-T.; Cebrian, A.; Brown, C.; Greenberg, D.; Shah, M.; Caldas, C.; Dunning, A.; Easton, D.; Ponder, B. Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J. Clin. Oncol. 2007, 25, 3015–3023. [Google Scholar] [CrossRef]
  105. Choi, Y.-J.; Lee, K.; Jeong, M.; Shin, Y.C.; Ko, S.-G. Metabolomic analysis of exosomes derived from lung cancer cell line H460 treated with SH003 and docetaxel. Metabolites 2022, 12, 1037. [Google Scholar] [CrossRef]
  106. Yin, Q.; Wang, L.; Yu, H.; Chen, D.; Zhu, W.; Sun, C. Pharmacological effects of polyphenol phytochemicals on the JAK-STAT signaling pathway. Front. Pharmacol. 2021, 12, 716672. [Google Scholar] [CrossRef] [PubMed]
  107. Liu, H.; Wang, Z.; Liu, Z. Formononetin restrains tumorigenesis of breast tumor by restraining STING-NF-κB and interfering with the activation of PD-L1. Discov. Med. 2024, 36, 613–620. [Google Scholar] [CrossRef] [PubMed]
  108. Tan, D.; Ma, N.; Wang, Y.; Li, X.; Xu, M. Reactive oxygen species in cancer: Mechanistic insights and therapeutic innovations. Cell Stress Chaperones 2025, 30, 100108. [Google Scholar]
  109. Jabalee, J.; Towle, R.; Garnis, C. The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications. Cells 2018, 7, 93. [Google Scholar] [CrossRef]
  110. Zhang, J.; Li, S.; Li, L.; Li, M.; Guo, C.; Yao, J.; Mi, S. Exosome and exosomal microRNA: Trafficking, sorting, and function. Genom. Proteom. Bioinform. 2015, 13, 17–24. [Google Scholar] [CrossRef]
  111. Marcus, M.E.; Leonard, J.N. FedExosomes: Engineering therapeutic biological nanoparticles that truly deliver. Pharmaceuticals 2013, 6, 659–680. [Google Scholar] [CrossRef]
  112. Karabay, A.Z.; Ozkan, T.; Karadag Gurel, A.; Koc, A.; Hekmatshoar, Y.; Sunguroglu, A.; Aktan, F.; Buyukbingöl, Z. Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2024, 397, 9701–9721. [Google Scholar] [CrossRef]
  113. Ferrari, P.; Scatena, C.; Ghilli, M.; Bargagna, I.; Lorenzini, G.; Nicolini, A. Molecular mechanisms, biomarkers and emerging therapies for chemotherapy resistant TNBC. Int. J. Mol. Sci. 2022, 23, 1665. [Google Scholar] [CrossRef]
  114. Mason, S.R.; Willson, M.L.; Egger, S.J.; Beith, J.; Dear, R.F.; Goodwin, A. Platinum-based chemotherapy for early triple-negative breast cancer. Cochrane Database Syst. Rev. 2023, 9. [Google Scholar] [CrossRef]
  115. Gao, T.; Hu, S.; Jiang, M.; Ou, G.; Zhong, R.; Sun, J.; Yang, Q.; Hu, K.; Gao, L. Combining network pharmacology and transcriptomics to validate and explore the efficacy and mechanism of Huayu Wan in treating non-small cell lung cancer. J. Ethnopharmacol. 2025, 347, 119724. [Google Scholar] [CrossRef] [PubMed]
  116. Liu, D.; Mu, Y.; Gao, F.; Zhang, Y.; Shen, Z.; Zhao, Z.; Zhang, P.; Lv, T.; Wang, Y.; Liu, Y. Multi-tissue metabolomics and network pharmacology study on the intervention of Danggui Buxue Decoction in mice with gemcitabine induced myelosuppression. J. Ethnopharmacol. 2025, 343, 119498. [Google Scholar] [CrossRef] [PubMed]
  117. Wu, S.; Xi, J.; Liu, Z.; Ding, Y. Clinical study of Shenqi Fuzheng decoction directional penetration for the treatment of cancer pain in advanced lung cancer patients. Cirugía Cir. 2025, 93, 6–12. [Google Scholar] [CrossRef]
  118. Mao, J.T.; Xue, B.; Fan, S.; Neis, P.; Qualls, C.; Massie, L.; Fiehn, O. Leucoselect phytosome modulates serum eicosapentaenoic acid, docosahexaenoic acid, and prostaglandin E3 in a phase I lung cancer chemoprevention study. Cancer Prev. Res. 2021, 14, 619–626. [Google Scholar] [CrossRef]
  119. Santos, E.S.; Rodriguez, E. Treatment considerations for patients with advanced squamous cell carcinoma of the lung. Clin. Lung Cancer 2022, 23, 457–466. [Google Scholar] [CrossRef] [PubMed]
  120. Wang, M.; Fu, Y.; Zhong, C.; Gacche, R.N.; Wu, P. Long non-coding RNA and Evolving drug resistance in lung cancer. Heliyon 2023, 9, e22591. [Google Scholar] [CrossRef]
  121. Zhu, Y.; Hu, Y.; Tang, C.; Guan, X.; Zhang, W. Platinum-based systematic therapy in triple-negative breast cancer. Biochim. Biophys. Acta (BBA)-Rev. Cancer 2022, 1877, 188678. [Google Scholar] [CrossRef]
  122. Wang, Z.; Tu, C.; Pratt, R.; Khoury, T.; Qu, J.; Fahey, J.W.; McCann, S.E.; Zhang, Y.; Wu, Y.; Hutson, A.D.; et al. A Presurgical-Window Intervention Trial of Isothiocyanate-Rich Broccoli Sprout Extract in Patients with Breast Cancer. Mol. Nutr. Food Res. 2022, 66, e2101094. [Google Scholar] [CrossRef]
  123. Ávila-Gálvez, M.; González-Sarrías, A.; Martínez-Díaz, F.; Abellán, B.; Martínez-Torrano, A.J.; Fernández-López, A.J.; Giménez-Bastida, J.A.; Espín, J.C. Disposition of Dietary Polyphenols in Breast Cancer Patients’ Tumors, and Their Associated Anticancer Activity: The Particular Case of Curcumin. Mol. Nutr. Food Res. 2021, 65, e2100163. [Google Scholar] [CrossRef] [PubMed]
  124. Jafari, F.; Izadi-Avanji, F.S.; Maghami, M.; Sarvizadeh, M. Topical use of chicory root extract gel on the incidence and severity of radiodermatitis in breast cancer patients: A randomized controled trial. Support. Care Cancer 2024, 32, 805. [Google Scholar] [CrossRef] [PubMed]
  125. Meneses, A.G.; Ferreira, E.B.; Vieira, L.A.C.; Bontempo, P.S.M.; Guerra, E.N.S.; Ciol, M.A.; Reis, P. Comparison of liposomal gel with and without chamomile to prevent radiation dermatitis in breast cancer patients: A randomized controlled trial. Strahlenther. Onkol. 2025, 201, 115–125. [Google Scholar] [CrossRef] [PubMed]
  126. Bounous, V.E.; Cipullo, I.; D’Alonzo, M.; Martella, S.; Franchi, D.; Villa, P.; Biglia, N.; Ferrero, A. A prospective, multicenter, randomized, double-blind placebo-controlled trial on purified and specific Cytoplasmic pollen extract for hot flashes in breast cancer survivors. Gynecol. Endocrinol. 2024, 40, 2334796. [Google Scholar] [CrossRef]
  127. Tanaka, M.; Tanaka, T.; Takamatsu, M.; Shibue, C.; Imao, Y.; Ando, T.; Baba, H.; Kamiya, Y. Effects of the Kampo medicine Yokukansan for perioperative anxiety and postoperative pain in women undergoing breast surgery: A randomized, controlled trial. PLoS ONE 2021, 16, e0260524. [Google Scholar] [CrossRef]
  128. Yang, Z.; Wang, L.; Xin, X.U.; Jie, L.I.; Shengli, H.U.; Ying, W. Clinical effect of Shugan Jieyu San for improving liver function and alleviating depression in patients with triple negative breast cancer. J. Tradit. Chin. Med. 2025, 45, 633–638. [Google Scholar] [CrossRef]
  129. Siddiquee, S.; McGee, M.A.; Vincent, A.D.; Giles, E.; Clothier, R.; Carruthers, S.; Penniment, M. Efficacy of topical Calendula officinalis on prevalence of radiation-induced dermatitis: A randomised controlled trial. Australas. J. Dermatol. 2021, 62, e35–e40. [Google Scholar] [CrossRef]
  130. Tang, Z.; Zhou, P.; Sun, H. Clinical Efficacy of Yiqi Yangyin Decoction Combined with Adjuvant Chemotherapy on the Postoperative Life Quality of Breast Cancer. Nutr. Cancer 2024, 76, 824–830. [Google Scholar] [CrossRef]
  131. Heydari, B.; Sheikhalishahi, S.; Hoseinzade, F.; Shabani, M.; Ramezani, V.; Saghafi, F. Topical Curcumin for Prevention of Radiation-Induced Dermatitis: A Pilot Double-Blind, Placebo-Controlled Trial. Cancer Investig. 2025, 43, 173–182. [Google Scholar] [CrossRef]
  132. Jiang, Y.; Liu, F.F.; Cai, Y.Q.; Zhang, P.; Yang, X.F.; Bi, X.Y.; Qin, R.Y.; Zhang, S.; Yin, J.H.; Shen, L.P.; et al. Oral Decoctions Based on Qi-Yin Syndrome Differentiation After Adjuvant Chemotherapy in Resected Stage ΙΙΙA Non-Small Cell Lung Cancer: A Randomized Controlled Trial. Integr. Cancer Ther. 2024, 23, 15347354241268271. [Google Scholar] [CrossRef] [PubMed]
  133. Liang, Q.; Tang, X.; Yu, J.; Xiong, M.; Zhu, H.; Xiong, L.; Zeng, R.; Yu, P. Clinical observation of Yiqi Qingdu prescription on the treatment of intermediate-stage and advanced non-small-cell lung cancer. J. Tradit. Chin. Med. 2021, 41, 308–315. [Google Scholar]
  134. Kwag, E.; Kim, S.D.; Shin, S.H.; Oak, C.; Park, S.J.; Choi, J.Y.; Hoon Yoon, S.; Kang, I.C.; Jeong, M.K.; Woo Lee, H.; et al. A Randomized, Multi-Center, Open Label Study to Compare the Safety and Efficacy between Afatinib Monotherapy and Combination Therapy with HAD-B1 for the Locally Advanced or Metastatic NSCLC Patients with EGFR Mutations. Integr. Cancer Ther. 2024, 23, 15347354241268231. [Google Scholar] [CrossRef]
  135. Ko, M.M.; Na, S.W.; Yi, J.M.; Jang, H.; Choi, C.M.; Lee, S.H.; Lee, S.Y.; Jeong, M.K. Effects of Bojungikki-Tang on immune response and clinical outcomes in NSCLC patients receiving immune checkpoint inhibitors: A randomized pilot study. BMC Cancer 2025, 25, 1229. [Google Scholar] [CrossRef] [PubMed]
  136. Lu, X.; Wang, A.; Chen, D.; Yang, M.; Zhang, Y.; Liu, M.; Zhang, X.; Li, Y.; Liu, D.; Wang, Y.; et al. Gegen Qinlian Tablets attenuate immune-related adverse events in NSCLC patients: A multi-center randomized controlled trial in China. Phytomedicine 2025, 145, 156968. [Google Scholar] [CrossRef]
  137. Ming, W.; Yun, Z. Clinical value of modified Shenling Baizhu powder in treating targeted therapy-induced diarrhea in non-small cell lung cancer. J. Tradit. Chin. Med. 2024, 44, 1000–1005. [Google Scholar] [CrossRef]
  138. Ruixin, W.U.; Qingliang, F.; Sisi, G.; Xianglong, W.; Mengjun, S.; Zhujun, M.; Yabin, G.; Ling, X.U.; Di, Z.; Changsheng, D. A pilot study of precision treatment for patients with lung cancer pain by Longteng Tongluo recipe using serum genomics. J. Tradit. Chin. Med. 2024, 44, 1006–1016. [Google Scholar] [CrossRef] [PubMed]
Cancers 17 03519 g001
Figure 1. Proposed and experimentally supported mechanisms of SH003 in regulating ferroptosis, redox signaling, and immune remodeling. In early-phase clinical testing (KCT0004770), SH003 administered with docetaxel demonstrated a favorable safety profile and potential therapeutic synergy, underscoring translational feasibility. Mechanistically, SH003 is proposed to remodel tumor-derived exosome cargo, thereby reprogramming the tumor–immune interface. Major features include: (i) repolarization of macrophages toward an M1 phenotype (iNOS, ARG1, CXCL10 upregulation); (ii) attenuation of regulatory T-cell–mediated suppression through reduced FOXP3, IL-10, and TGF-β; (iii) restoration of CD8+ T-cell effector function via STAT3 inhibition and PD-L1 downregulation, accompanied by enhanced CD8+/NK infiltration (in synergy with docetaxel); and (iv) activation of NK cells with increased NKG2D, PRF1, and GZMB expression. Representative exosomal miRNAs (miR-200c, miR-21) are illustrated as cargo mediators linking redox signaling to immune remodeling. Dashed outlines indicate hypothesized or incompletely validated pathways. Overall, SH003 is depicted as a model phytomedicine that integrates exosomal regulation and immune modulation within a biomarker-informed therapeutic framework. Abbreviations: serine/threonine kinase (Akt); arginase (ARG); cluster of differentiation 8 positive T lymphocyte (CD8+ T cell); C-X-C motif chemokine ligand 10 (CXCL10); forkhead box P3 (FOXP3); granzyme B (GZMB); inducible nitric oxide synthase (iNOS); interferon-gamma (IFN-γ); classically activated macrophage (pro-inflammatory) (M1 macrophage); alternatively activated macrophage (anti-inflammatory) (M2 macrophage); natural killer cell (NK cell); natural killer group 2 member D (NKG2D); perforin 1 (PRF1); regulatory T cell (Treg); tumor-associated macrophage (TAM); T-cell receptor (TCR); transforming growth factor-beta (TGF-β). Red arrows indicate downregulation, and blue arrows indicate upregulation of the corresponding proteins or pathways. Created in BioRender. Kim, B. (2025) https://BioRender.com/6e3e802 (accessed on 28 October 2025).
Figure 1. Proposed and experimentally supported mechanisms of SH003 in regulating ferroptosis, redox signaling, and immune remodeling. In early-phase clinical testing (KCT0004770), SH003 administered with docetaxel demonstrated a favorable safety profile and potential therapeutic synergy, underscoring translational feasibility. Mechanistically, SH003 is proposed to remodel tumor-derived exosome cargo, thereby reprogramming the tumor–immune interface. Major features include: (i) repolarization of macrophages toward an M1 phenotype (iNOS, ARG1, CXCL10 upregulation); (ii) attenuation of regulatory T-cell–mediated suppression through reduced FOXP3, IL-10, and TGF-β; (iii) restoration of CD8+ T-cell effector function via STAT3 inhibition and PD-L1 downregulation, accompanied by enhanced CD8+/NK infiltration (in synergy with docetaxel); and (iv) activation of NK cells with increased NKG2D, PRF1, and GZMB expression. Representative exosomal miRNAs (miR-200c, miR-21) are illustrated as cargo mediators linking redox signaling to immune remodeling. Dashed outlines indicate hypothesized or incompletely validated pathways. Overall, SH003 is depicted as a model phytomedicine that integrates exosomal regulation and immune modulation within a biomarker-informed therapeutic framework. Abbreviations: serine/threonine kinase (Akt); arginase (ARG); cluster of differentiation 8 positive T lymphocyte (CD8+ T cell); C-X-C motif chemokine ligand 10 (CXCL10); forkhead box P3 (FOXP3); granzyme B (GZMB); inducible nitric oxide synthase (iNOS); interferon-gamma (IFN-γ); classically activated macrophage (pro-inflammatory) (M1 macrophage); alternatively activated macrophage (anti-inflammatory) (M2 macrophage); natural killer cell (NK cell); natural killer group 2 member D (NKG2D); perforin 1 (PRF1); regulatory T cell (Treg); tumor-associated macrophage (TAM); T-cell receptor (TCR); transforming growth factor-beta (TGF-β). Red arrows indicate downregulation, and blue arrows indicate upregulation of the corresponding proteins or pathways. Created in BioRender. Kim, B. (2025) https://BioRender.com/6e3e802 (accessed on 28 October 2025).
Cancers 17 03519 g001
Cancers 17 03519 g002
Figure 2. Integrated redox–ferroptosis–immune modulation by SH003. SH003 phytochemicals (decursin, formononetin, baicalein, cucurbitacin D, luteolin) target interconnected pathways including ER stress, NRF2–KEAP1 antioxidant signaling, ferroptosis, and autophagy. These effects converge on immune remodeling via STAT3/PD-L1 suppression and enhanced CD8+ T/NK infiltration. Representative biomarker alterations (GPX4, NRF2, CHOP, TRX2) highlight its potential for patient stratification. Translationally, SH003 has progressed to Phase I clinical trials, establishing safety and feasibility. Abbreviations: neutrophil extracellular trap–mediated cell death (NETosis); Sequestosome 1 (p62/SQSTM1); Thioredoxin 2 (TRX2); Unc-51 like autophagy activating kinase 1 (ULK1); Vacuolar protein sorting 34 (VPS34). Red arrows indicate downregulation, blue arrows indicate upregulation of the corresponding proteins or pathways; bidirectional arrows represent feedback interactions between the indicated pathways; red curved arrows represent inhibitory regulation. Created in BioRender. Kim, B. (2025) https://BioRender.com/r9g2odr (accessed on 28 October 2025).
Figure 2. Integrated redox–ferroptosis–immune modulation by SH003. SH003 phytochemicals (decursin, formononetin, baicalein, cucurbitacin D, luteolin) target interconnected pathways including ER stress, NRF2–KEAP1 antioxidant signaling, ferroptosis, and autophagy. These effects converge on immune remodeling via STAT3/PD-L1 suppression and enhanced CD8+ T/NK infiltration. Representative biomarker alterations (GPX4, NRF2, CHOP, TRX2) highlight its potential for patient stratification. Translationally, SH003 has progressed to Phase I clinical trials, establishing safety and feasibility. Abbreviations: neutrophil extracellular trap–mediated cell death (NETosis); Sequestosome 1 (p62/SQSTM1); Thioredoxin 2 (TRX2); Unc-51 like autophagy activating kinase 1 (ULK1); Vacuolar protein sorting 34 (VPS34). Red arrows indicate downregulation, blue arrows indicate upregulation of the corresponding proteins or pathways; bidirectional arrows represent feedback interactions between the indicated pathways; red curved arrows represent inhibitory regulation. Created in BioRender. Kim, B. (2025) https://BioRender.com/r9g2odr (accessed on 28 October 2025).
Cancers 17 03519 g002
Table 1. Redox-modulating mechanisms and translational roles of SH003 constituents.
Table 1. Redox-modulating mechanisms and translational roles of SH003 constituents.
CompoundChelation PotentialBiomarkerKey MechanismTranslational
Relevance		ModelReference
Baicalein (5,6,7-trihydroxy flavone core)Possible Fe2+ binding via 5-OH/4-keto; weaker than catechol flavonoidsNRF2/
GPX4 redox balance		Promotes ROS-driven cytotoxicity; inhibits JAK2/STAT3 → GPX4 suppression → ferroptosisBiomarker modulation (NRF2/GPX4); ferroptosis sensitizerHCT116, DLD1,
CRC xenograft		[67]
Chrysoeriol (3″-methoxy-4″,5,7-trihydroxy flavone)Lacks catechol;
Fe2+ binding via
5-OH/4-keto 		Inhibits TNFα-induced EGR-1/CYP19; reduces estrogen biosynthesisSupportive flavonoid; potential chemopreventive adjuvant in ER+ breast cancerMCF-7[68]
Cucurbitacin B/D
(Triterpenoid)		No strong chelation; enhances ferroptosis via SLC7A11–GPX4 suppression and ROS accumulationGPX4, SLC7A11 STAT3 inhibition
(CuB strong;
CuD possible); suppression of SLC7A11–GPX4 		Ferroptosis biomarker (GPX4↓); immune modulation via STAT3 (CuB evidence, CuD inferred)MCF-7, MDA-MB-231,
CNE1 xenograft		[69,70]
Decursin (pyranocoumarin)No catechol chelation; redox modulation via ER stressCHOP Induces ER stress (PERK–eIF2α–ATF4–CHOP); Nox4-mediated ROS; caspase-3/9 activationBiomarker: CHOP↑; ER stress–apoptosis driver; potential chemo-combination (oxaliplatin)HCT-116, HCT-8, MCF-7, MDA-MB-231, LNCaP, DU145, PC3, PANC-1, MiaPaCa-2[71,72]
Formononetin (isoflavone)No catechol chelationNRF2, PI3KModulates KEAP1–NRF2 (GSTP1↑); PI3K/Akt–NRF2 linkage; ER stress (context-dependent)Biomarker: NRF2 pathway; normal tissue protection; safe in oxaliplatin combinationsA549, HCT116, HT29, MCF-7, SH-SY5Y, CRC xenograft[35,41,73]
Hispidulin (4″-methoxy-5,7-dihydroxy)Limited Fe2+ binding (5,7-dihydroxy)UPR/
CHOP		ROS-dependent apoptosis via mitochondrial dysfunction and ER stress (CHOP↑)Translational apoptosis driver (UPR biomarker: CHOP↑, p-eIF2α↑)HepG2, A549,
NCI-H460		[74,75]
Luteolin (3″,4″-dihydroxy catechol moiety, 5,7-dihydroxy)Strong Fe2+ chelation
(catechol group)		GPX4, NRF2Induces oxidative stress; downregulates NRF2–KEAP1–Cul3; triggers GPX4-dependent ferroptosisFerroptosis biomarkers (GPX4↓, lipid peroxidation, GSH/GSSG); immune activation (M1 polarization, CD8+ T-cell infiltration)PC3, DU145; MC38, CT26; syngeneic mouse[76,77]
Most mechanisms summarized here are supported by preclinical SH003 studies or constituent-derived evidence unless otherwise indicated. Arrows indicate direction of regulation: ↓ downregulation, ↑ upregulation. Abbreviations: Colorectal cancer (CRC), Cullin-3 (Cul3); Early growth response 1 (EGR-1); Estrogen receptor–positive (ER+); Reduced glutathione (GSH)/Oxidized glutathione (GSSG); Glutathione S-transferase Pi 1 (GSTP1); NAD(P)H quinone dehydrogenase 1 (NQO1); NADPH oxidase 4 (Nox4); Solute carrier family 7 member 11 (SLC7A11); Tumor necrosis factor alpha (TNFα).
Table 2. Key redox pathways targeted by SH003 and associated biomarkers with translational relevance.
Table 2. Key redox pathways targeted by SH003 and associated biomarkers with translational relevance.
TargetSH003
Modulation		Mechanistic PathwaysBiomarkersTranslational
Relevance		Evidence LevelRefs:
Trx1/Trx2TrxR inhibition (baicalein, reported); TRX2 speculative/unvalidated ↑ ASK1 activation, ↑ p53 stabilization, apoptosis/senescenceTrx1/Trx2 ratio, oxidation stateEstablished oxidative stress marker (clinical correlation); potential stratifierClinical correlation[81]
GPX4Inhibition by cucurbitacin D ↑ Ferroptotic cell deathGPX4 proteinPredictive marker for ferroptosis sensitivity (TNBC, NSCLC)MDA-MB-231, Hs578T; A549, H460[79]
NRF2Suppression by baicalein, formononetin↓ antioxidant genes, ↑ ROSNRF2 localization, HO-1/NQO1Context-dependent marker of adaptation and therapy resistanceHK-2, Wistar rat AKI[87]
CHOPUpregulation by decursin, hispidulin↑ ER stress–mediated apoptosisCHOP expressionApoptosis stress marker (HCC, prostate, cervical models)HepG2, PC-3, DU145, HeLa,
PC-3 xenograft, HepG2 xenograft		[88]
TXNIPIndirect upregulation↑ ASK1 activation, oxidative apoptosisTXNIP mRNA/
protein 		Oxidative imbalance marker; therapeutic monitoring in nephrotoxicityHK-2, Wistar rat[89]
Evidence levels range from constituent inference to preclinical validation; only TRX1/TRX2 exhibit clinical correlation to date. Arrows indicate direction of regulation: ↓ downregulation, ↑ upregulation. Abbreviations: Apoptosis signal-regulating kinase 1 (ASK1); Cucurbitacin B (CuB); Cucurbitacin D (CuD); Docetaxel (DTX); Glycogen synthase kinase 3 beta (GSK3β); Heme oxygenase 1 (HO-1); Messenger RNA (mRNA); NAD(P)H quinone dehydrogenase 1 (NQO1); Tumor-associated macrophage (TAM); Thioredoxin reductase (TrxR); Thioredoxin 1/Thioredoxin 2 (Trx1/Trx2); Thioredoxin-interacting protein (TXNIP).
Table 3. Comparative clinical focus of natural products in breast and lung cancer and translational positioning of SH003.
Table 3. Comparative clinical focus of natural products in breast and lung cancer and translational positioning of SH003.
Cancer TypeMain Clinical Focus
of Natural Products		Example InterventionsSH003 Positioning
Breast cancerSupportive care → QoL improvement, radiodermatitis prevention, perioperative anxiety, menopausal symptom relief, depression managementBroccoli sprout extract (isothiocyanates) [122], Polyphenol capsules (Curcumin, isoflavones, lignans) [123], Chicory root extract [124], chamomile gel [125], PureCyTonin (pollen extract) [126], Yokukansan (Kampo) [127], Shugan Jieyu San [128], calendula [129], Yiqi Yangyin decoction +chemo [130], curcumin [131].Tumor-modifying phytomedicine → Mechanistic redox disruption & immune modulation [9].
Lung cancerDisease-modifying strategies → Tumor suppression, drug resistance overcoming, immune modulation, ferroptosis inductionOral decoctions after adjuvant chemo [132], Yiqi Qingdu prescription [133], multi-herbal combinations [134], BJIKT + ICIs [135], GQT + ICIs [136], Shenling Baizhu powder [137], LTTL [138].Ferroptosis induction + NRF2 adaptation + immune remodeling → Translational bridge: preclinical evidence → Phase I feasibility [9].
Abbreviations: Bojungikki-tang (BJIKT); Chinese herbal medicine (CHM); Gegen Qinlian Tablets (GQT); Immune checkpoint inhibitors (ICIs); Longteng Tongluo recipe (LTTL); Quality of life (QoL).
Table 4. Proposed exploratory trial design for SH003 combinations in NSCLC/TNBC.
Table 4. Proposed exploratory trial design for SH003 combinations in NSCLC/TNBC.
SectionItemProposed Content
Population/SettingIndicationsEGFR-mutant NSCLC or TNBC with measurable, advanced disease; prior standard therapy permitted.
Eligibility highlightsECOG 0–1; adequate organ function; archival or fresh tumor tissue available for biomarker testing.
Arms
(Phase Ib/II)		Arm ADocetaxel + SH003.
Arm B (control)Docetaxel alone.
Exploratory cohortAnti-PD-1/PD-L1 + SH003 in PD-1–refractory subsets (signal-seeking).
Primary endpointsPhase IbDose-limiting toxicities (DLTs), MTD, RP2D (combination).
Phase IIProgression-free survival (PFS; RECIST 1.1).
Key secondary endpointsEfficacy & safetyORR, DoR, DCR, OS; safety (AE/SAE, irAEs); patient-reported outcomes (QoL).
Stratification factors (pre-specified)Genomic/biologicKEAP1/NFE2L2 genotype; NRF2 target-gene signature (high vs. low); GPX4 expression (low vs. high); PD-L1 status.
ClinicalSmoking history (to aid interpretation of metabolomic/circulating biomarker signals).
Correlative/Pharmacodynamic endpointsRedox/ferroptosisTumor SLC7A11, GPX4; lipid peroxidation markers (4-HNE, MDA); NRF2 targets (NQO1, GCLC).
ER-stress/mitochondriaCHOP (DDIT3); thioredoxin system (Trx/TrxR; including TRX2) as mitochondrial redox readouts.
Immune remodelingCD8+ infiltration; M1/M2 ratio; p-STAT3; PD-L1 (IHC).
Circulating biomarkersSerum SQSTM1 (p62); exosome-based miRNA panel (e.g., miR-200c/21/210/96); cfDNA/ctDNA.
Exosome metabolomicsExploratory predictive biomarker collection in combination arms; functional immunologic causality to be tested prospectively.
Dosing/SafetySH003Start at safe monotherapy exposure from prior Phase I; stepwise escalation to combination RP2D (e.g., 2400–4800 mg/day), with close hepatic/hematologic monitoring.
DocetaxelStandard dose and schedule per label or institutional practice.
Drug–drug considerationsMonitor for metabolism/transport interactions; pre-specify management of overlapping toxicities.
Interim/StatisticsInterim analysesPlanned futility/safety looks at pre-defined information fractions.
Subgroup testingPre-specified interaction tests for KEAP1/NFE2L2 strata; estimate differential benefit in NRF2-hyperactivated tumors.
Abbreviations: Adverse event (AE); Circulating tumor DNA (ctDNA); Disease control rate (DCR); Duration of response (DoR); Dose-limiting toxicity (DLT); Immunohistochemistry (IHC); Immune-related adverse event (irAE); Malondialdehyde (MDA); Maximum tolerated dose (MTD); Objective response rate (ORR); Overall survival (OS); Progression-free survival (PFS); Quality of life (QoL); Recommended Phase 2 dose (RP2D).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Park, M.N.; Fahim, M.M.H.; Kang, H.N.; Bae, H.; Rani, A.; Nurkolis, F.; Tallei, T.E.; Ko, S.-G.; Kim, B. SH003 as a Redox-Immune Modulating Phytomedicine: A Ferroptosis Induction, Exosomal Crosstalk, and Translational Oncology Perspective. Cancers 2025, 17, 3519. https://doi.org/10.3390/cancers17213519

AMA Style

Park MN, Fahim MMH, Kang HN, Bae H, Rani A, Nurkolis F, Tallei TE, Ko S-G, Kim B. SH003 as a Redox-Immune Modulating Phytomedicine: A Ferroptosis Induction, Exosomal Crosstalk, and Translational Oncology Perspective. Cancers. 2025; 17(21):3519. https://doi.org/10.3390/cancers17213519

Chicago/Turabian Style

Park, Moon Nyeo, Md. Maharub Hossain Fahim, Han Na Kang, Hanul Bae, Amama Rani, Fahrul Nurkolis, Trina E. Tallei, Seong-Gyu Ko, and Bonglee Kim. 2025. "SH003 as a Redox-Immune Modulating Phytomedicine: A Ferroptosis Induction, Exosomal Crosstalk, and Translational Oncology Perspective" Cancers 17, no. 21: 3519. https://doi.org/10.3390/cancers17213519

APA Style

Park, M. N., Fahim, M. M. H., Kang, H. N., Bae, H., Rani, A., Nurkolis, F., Tallei, T. E., Ko, S.-G., & Kim, B. (2025). SH003 as a Redox-Immune Modulating Phytomedicine: A Ferroptosis Induction, Exosomal Crosstalk, and Translational Oncology Perspective. Cancers, 17(21), 3519. https://doi.org/10.3390/cancers17213519

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop