A homologous membrane-camouflaged self-assembled nanodrug for synergistic antitumor therapy.

Limited success has been achieved in ferroptosis-induced cancer treatment due to the challenges related to low production of toxic reactive oxygen species (ROS) and inherent ROS resistance in cancer cells. To address this issue, a self-assembled nanodrug have been investigated that enhances ferroptosis therapy by increasing ROS production and reducing ROS inhibition. The nanodrug is constructed by allowing doxorubicin (DOX) to interact with Fe2+ through coordination interactions, forming a stable DOX-Fe2+ chelate, and this chelate further interacts with sorafenib (SRF), resulting in a stable and uniform nanoparticle. In tumor cells, overexpressed glutathione (GSH) triggers the disassembly of nanodrug, thereby activating the drug release. Interestingly, the released DOX not only activates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) to produce abundant H2O2 production for enhanced ROS production, but also acts as a chemotherapeutics agent, synergizing with ferroptosis. To enhance tumor selectivity and improve the blood clearance, the nanodrug is coated with a related cancer cell membrane, which enhances the selective inhibition of tumor growth and metastasis in a B16F10 mice model. Our findings provide valuable insights into the rational design of self-assembled nanodrug for enhanced ferroptosis therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: Ferroptosis is a non-apoptotic form of cell death induced by the iron-regulated lipid peroxides (LPOs), offering a promising potential for effective and safe anti-cancer treatment. However, two significant challenges hinder its clinical application: 1) The easily oxidized nature of Fe2+ and the low concentration of H2O2 leads to a low efficiency of intracellular Fenton reaction, resulting in poor therapeutic efficacy; 2) The instinctive ROS resistance of cancer cells induce drug resistance. Therefore, we developed a simple and high-efficiency nanodrug composed of self-assembling by Fe2+ sources, H2O2 inducer and ROS resistance inhibitors. This nanodrug can effectively deliver the Fe2+ sources into tumor tissue, enhance intracellular concentration of H2O2, and reduce ROS resistance, achieving a high-efficiency, precise and safe ferroptosis therapy.

Programmable Singlet Oxygen Battery for Automated Photodynamic Therapy Enabled by Pyridone-Pyridine Tautomer Engineering.

The efficacy of photodynamic therapy is hindered by the hypoxic environment in tumors and limited light penetration depth. The singlet oxygen battery (SOB) has emerged as a promising solution, enabling oxygen- and light-independent 1O2 release. However, conventional SOB systems typically exhibit an "always-ON" 1O2 release, leading to potential 1O2 leakage before and after treatment. This not only compromises therapeutic outcomes but also raises substantial biosafety concerns. In this work, we introduce a programmable singlet oxygen battery, engineered to address all the issues discussed above. The concept is illustrated through the development of a tumor-microenvironment-responsive pyridone-pyridine switch, PyAce, which exists in two tautomeric forms: PyAce-0 (pyridine) and PyAce (pyridone) with different 1O2 storage half-lives. In its native state, PyAce remains in the pyridone form, capable of storing 1O2 (t1/2 = 18.5 h). Upon reaching the tumor microenvironment, PyAce is switched to the pyridine form, facilitating rapid and thorough 1O2 release (t1/2 = 16 min), followed by quenched 1O2 release post-therapy. This mechanism ensures suppressed 1O2 production pre- and post-therapy with selective and rapid 1O2 release at the tumor site, maximizing therapeutic efficacy while minimizing side effects. The achieved "OFF-ON-OFF" 1O2 therapy showed high spatiotemporal selectivity and was independent of the oxygen supply and light illumination.

Correction: Intracellular regulation of zinc by metal-organic framework-mediated genome editing for prostate cancer therapy.

Correction for 'Intracellular regulation of zinc by metal-organic framework-mediated genome editing for prostate cancer therapy' by Yanan Xue et al., Biomater. Sci., 2023, https://doi.org/10.1039/d3bm00002h.

Erratum: Inflammation conditional genome editing mediated by the CRISPR-Cas9 system.

[This corrects the article DOI: 10.1016/j.isci.2023.106872.].

Intracellular regulation of zinc by metal-organic framework-mediated genome editing for prostate cancer therapy.

Normal prostate tissues generally exhibit a higher level of zinc to maintain their special "citrate-producing" metabolism, while its level dramatically decreases during prostate tumorigenesis. Despite the significant antitumor effects, the intracellular accumulation of zinc in prostate cancer cells also promotes the expression of ZNT1, which in turn results in the efflux of zinc and attenuated cytotoxicity against cancer cells. To solve the dilemma, we developed a 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA)-decorated zeolitic imidazolate framework-8 (ZIF8), which is able to load plasmid DNA encoding the Cas9 editor and single-guide RNA to form Cas9@ZIF8-DUPA nanocomplexes. The intracellular delivery of Cas9@ZIF8-DUPA simultaneously increases the level of zinc and inhibits the ZNT-1 function by disrupting the SLC30A1 gene to prevent the efflux of zinc in prostate cancer cells. Due to the high affinity between DUPA and the prostate-specific membrane antigen, Cas9@ZIF8-DUPA nanocomplexes exhibit excellent prostate tumor-targeting ability. The internalization and degradation of Cas9@ZIF8-DUPA not only release free zinc and Cas9 editors, but also reduce zinc efflux through Cas9-mediated genome editing that disables the function of ZNT1. As a result, Cas9@ZIF8-DUPA nanocomplexes exhibit significant antitumor activity and extended survival in the mouse model bearing prostate tumors. The current platform offers an alternative therapeutic strategy and holds tremendous translational potential as an anticancer nanomedicine for prostate cancer treatment.

Inflammation conditional genome editing mediated by the CRISPR-Cas9 system.

The specificity of CRISPR-Cas9 in response to particular pathological stimuli remains largely unexplored. Hence, we designed an inflammation-inducible CRISPR-Cas9 system by grafting a sequence that binds with NF-κB to the CRISPR-Cas9 framework, termed NBS-CRISPR. The genetic scissor function of this developed genome-editing tool is activated on encountering an inflammatory attack and is inactivated or minimized in non-inflammation conditions. Furthermore, we employed this platform to reverse inflammatory conditions by targeting the MyD88 gene, a crucial player in the NF-κB signaling pathway, and achieved impressive therapeutic effects. Finally, during inflammation, P65 (RELA) can translocate to the nucleus from the cytoplasm. Herein, to avoid Cas9 leaky DNA cleavage activity i, we constructed an NBS-P65-CRISPR system expressing the Cas9-p65 fusion protein. Our inflammation inducible Cas9-mediated genome editing strategy provides new perspectives and avenues for pathological gene interrogation.

A self-assembly nano-prodrug for triple-negative breast cancer combined treatment by ferroptosis therapy and chemotherapy.

Chemotherapeutics have been recommended as the standard protocol for inoperable patients with triple-negative breast cancer (TNBC) at advanced stage, yet limited success has been achieved in prolonging survival rates by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Ferroptosis has become a powerful modality of no-apoptotic cell death, which can effectively evade chemo-resistance in apoptotic pathways. Herein, we propose an active-targeting small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and GPX4 inhibitor (RSL3) to overcome the chemo-resistance from traditional apoptotic pathways. In this nano-prodrug, the disulfide linkage not only serves as a GSH-responsive trigger, but also exhibits a stable self-assembly behavior that forms nanoparticle. Interestingly, the RSL3 can be loaded during this self-assembly process that forms a three-components nano-prodrug. In tumor environment, the high GSH level can disassemble the nano-prodrug to trigger the release of the parent drug, which can improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis. In different TNBC mice models, the nano-prodrug is encapsulated into RGD-modified phospholipid micelles (DSPE-PEG2000-RGD) and exhibits high anti-tumor and anti-metastasis efficacy, especially in orthotopic models. The application of ferroptosis to assist the enhancement of chemotherapeutics may serve as a promising strategy for TNBC treatment. STATEMENT OF SIGNIFICANCE: Chemotherapeutics have been recommended as the standard of care for palliative and adjuvant treatment in patients with triple-negative breast cancer (TNBC), yet limited success has been achieved in prolonging the overall survival of patients by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Thus, the co-delivery of the apoptosis and ferroptosis drug may overcome or evade the resistance in chemotherapy-induced apoptotic pathways and provide a promising strategy to combat TNBC. In this work, we developed a small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and ferroptosis resistance inhibitor (RSL3), which could overcome the chemo-resistance and improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis.

A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.

Membrane-camouflaged supramolecular nanoparticles for co-delivery of chemotherapeutic and molecular-targeted drugs with siRNA against patient-derived pancreatic carcinoma.

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This "all-in-one" delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.

CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non-Small Cell Lung Cancer.

SIGNIFICANCE: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non-small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882.

A small-molecule self-assembled nanodrug for combination therapy of photothermal-differentiation-chemotherapy of breast cancer stem cells.

The combination therapy with different treatment modalities has been widely applied in the clinical applications of cancer treatment. However, it stills a considerable challenge to achieve co-delivery of different drugs because of distinct drug encapsulation mechanisms, low drug loading, and high excipient-related toxicity. Cancer stem cells (CSCs) are closely related to tumor metastasis and recurrence due to high chemoresistance. Herein, we report a stimuli-responsive and tumor-targeted small-molecule self-assembled nanodrug for the combination therapy against CSCs and normal cancer cells. The hydrophobic differentiation-inducing agent (all-trans retinoic acid, ATRA) and hydrophilic anticancer drug (irinotecan, IRI) constitute this amphiphilic nanodrug, which could self-assemble into stable nanoparticles and encapsulate the photothermal agent IR825. Upon cellular uptake, this nanodrug display good release profiles in response to acid and esterase microenvironments by ester linkage. The released drugs not only increase chemotherapy sensitivity by the differentiation of CSCs into non-CSCs, but also exhibit superior cytotoxicity in cancer cells. In addition, IR825 within this nanodrug enables in vivo fluorescence/photoacoustic (PA) imaging allowing for tracking drug distribution. Moreover, the DSPE-PEG-RGD-functionalized nanodrug displayed high tumor accumulation and good biocompatibility, enabling efficient inhibition of tumor growth and tumor metastasis in tumor-bearing mice.

Exosomes and their roles in the chemoresistance of pancreatic cancer.

Pancreatic cancer (PC) remains one of the most lethal human malignancies worldwide. Due to the insidious onset and the rapid progression, most patients with PC are diagnosed at an advanced stage rendering them inoperable. Despite the development of multiple promising chemotherapeutic agents as recommended first-line treatment for PC, the therapeutic efficacy is largely limited by unwanted drug resistance. Recent studies have identified exosomes as essential mediators of intercellular communications during the occurrence of drug resistance. Understanding the underlying molecular mechanisms and complex signaling pathways of exosome-mediated drug resistance will contribute to the improvement of the design of new oncologic therapy regimens. This review focuses on the intrinsic connections between the chemoresistance of PC cells and exosomes in the tumor microenvironment (TME).

Chemically modified magnetic immobilized phospholipase A1 and its application for soybean oil degumming.

In this paper, the free Phospholipase A1 (PLA1) was immobilized on a magnetic carrier. The average particle diameter of the magnetic carrier was 97 ± 1.3 nm, and the average particle diameter of the magnetically immobilized PLA1 was 105 nm ± 1.3 nm. The enzyme activity was 1940.5 U/g. The magnetic enzyme was chemically modified with formaldehyde, dextran-aldehyde, and dextran-aldehyde-glycine. The proportions of primary amino groups in the modified magnetic immobilized enzyme PLA1 were 0, 53.5% and 47.3%, respectively. The optimum pH of the enzyme after chemical modification was 6.5. When the system temperature was 60 °C, the magnetically immobilized PLA1 modified with dextran-aldehyde-glycine had the optimal activity and stability. This chemically modified magnetic immobilized PLA1 was applied to soybean oil degumming at 60 °C, 6.5 h (reaction time), and 0.10 mg/kg (enzyme dosage). The phosphorus content in the degummed oil was 9.2 mg/kg. The relative enzyme activity was 77.6% after 7 reuses which would be potentially advantageous for industrial applications. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s13197-021-05017-4).

A systematic review and meta-analysis: pulmonary mycosis pathogen distribution.

BACKGROUND: This study sought to systematically evaluate the distribution characteristics and high-risk factors of pulmonary mycosis pathogens, and provide evidence for the clinical treatment and prognosis of patients with pulmonary mycosis. METHODS: The Embase, Ovid, PubMed, Medline, and Springer databases were searched to find publications on the distribution characteristics and high-risk factors of pulmonary mycosis pathogens that had been published between the establishment of the databases and April 1, 2021. The Cochrane Handbook 5.0.2 was used to evaluate the risk of bias of the articles included in this study, and Review Manager 5.3 was used to conduct a meta-analysis of the included articles. RESULTS: Eleven articles were included in this study, comprising 6,415 subjects. The meta-analysis results showed that pathogen infection significantly increased the mortality of patients [MD =2.67; 95% confidence interval (CI): (1.52, 4.68); Z=3.43; P=0.0006]. Patient age was significantly correlated with the incidence of pulmonary mycosis [MD =1.21; 95% CI: (0.78, 1.86); Z=0.84; P=0.40]. The use of antibiotics was significantly correlated to the incidence of pulmonary mycosis [MD =1.41; 95% CI: (1.15, 1.72); Z=3.30; P=0.001]. Glucocorticoid use was significantly correlated to the incidence of pulmonary mycosis [MD =1.81; 95% CI: (1.13, 2.91); Z=2.45; P=0.01]. However, gender had no obvious correlation with the incidence of pulmonary mycosis [MD =1.21; 95% CI: (0.78, 1.86); Z=0.84; P=0.40]. Further, no correlation was found between smoking history and the incidence of pulmonary mycosis [MD =0.86; 95% CI: (0.51, 1.45); Z=0.57; P=0.57]. DISCUSSION: The main types of bacterial infections in patients with pulmonary mycosis were Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Candida albicans, and Helicobacter pylori. In addition to the lungs, pathogens were found to be distributed in the intestines, urinary tract, and digestive tract. Additionally, patient age, antibiotic use, and glucocorticoid use increased the incidence of pulmonary mycosis. Thus, these factors should be paid attention to in the clinical treatment of patients with pulmonary mycosis.

Delivery of a system xc- inhibitor by a redox-responsive levodopa prodrug nanoassembly for combination ferrotherapy.

A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system xc-, a key regulator for ferroptosis, to amplify the therapeutic efficacy of cancer ferrotherapy. The prodrug nanosystem is assembled between sulfasalazine (SSZ, a ferroptosis resistance inhibitor) and disulfide-bridged levodopa (DSSD) that can chelate Fe2+ ions to form SSZ-Fe2+@DSSD, and the resulting nanoassembly can not only inhibit ferroptosis resistance, but also generate ROS in the tumor microenvironment. Whereas the prodrug nanosystem is stable in the physiological environment, it becomes unstable in the tumoral and intracellular reductive microenvironment, where the disulfide linkers are disrupted by high levels of glutathione (GSH), triggering the release of active Fe2+ and SSZ. Under the Fenton reaction, the released Fe2+ thus can induce ferroptosis, which is amplified by SSZ-mediated inhibition of ferroptosis resistance to synergistically improve the therapeutic efficacy of ferroptosis. Our study thus provides an innovative prodrug strategy to advance anticancer ferroptosis.

Case Report: Clinical Responses to Tislelizumab as a First-Line Therapy for Primary Hepatocellular Carcinoma With B-Cell Indolent Lymphoma.

Background: As an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin's lymphoma (NHL) is rare, especially in the treatment of ICIs. Case presentation: A 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment. Conclusion: Tislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.

Reprogramming the Tumor Microenvironment through Second-Near-Infrared-Window Photothermal Genome Editing of PD-L1 Mediated by Supramolecular Gold Nanorods for Enhanced Cancer Immunotherapy.

A photothermal genome-editing strategy is described to improve immune checkpoint blockade (ICB) therapy by CRISPR/Cas9-mediated disruption of PD-L1 and mild-hyperthermia-induced activation of immunogenic cell death (ICD). This strategy relies on a supramolecular cationic gold nanorod that not only serves as a carrier to deliver CRISPR/Cas9 targeting PD-L1, but also harvests the second near-infrared-window (NIR-II) light and converts into mild hyperthermia to induce both ICD and gene expression of Cas9. The genomic disruption of PD-L1 significantly augments ICB therapy by improving the conversion of dendritic cells to T cells, followed by promoting the infiltration of cytotoxic T lymphocytes into tumors, thereby reprogramming immunosuppressive tumor microenvironment into immunoactive one. Such a therapeutic modality greatly inhibits the activity of primary and metastatic tumors and exhibits long-term immune memory effects against both rechallenged and recurrent tumors. The current therapeutic strategy for synergistic PD-L1 disruption and ICD activation represents an appealing way for cancer immunotherapy.

Enzyme-assisted Aqueous Extraction of Oil from Rice Germ and its Physicochemical Properties and Antioxidant Activity.

Enzyme-assisted aqueous extraction of rice germ oil (RGO) was performed in this study. The physicochemical properties, fatty acid composition, bioactive substances and antioxidant activity of RGO were analyzed. An enzyme composed of alcalase and cellulase (1:1, w/w) was found to be the most effective in the extraction yield of oil. The optimal oil yield of 22.27% was achieved under the conditions of an enzyme concentration of 2% (w/w), incubation time of 5 h, incubation temperature of 50°C, water to seed ratio of 5:1, and pH 6.0. The predominant fatty acids of RGO were oleic acid (39.60%), linoleic acid (34.20%) and palmitic acid (20.10%). The total saturated fatty acid (SFA), monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) composition of RGO were 22.50%, 39.60% and 36.00%, respectively. RGO yielded a high content of γ-oryzanol (530 mg/100 g oil), tocotrienol (62.96 mg/100 g oil), tocopherol (23.24 mg/100 g oil) and a significant amount of phytosterol (372.14 mg/100 g oil). It exhibited notable antioxidant activities with IC50 values of 32.37 and 41.13 mg/mL, according to the DPPH radical scavenging assay and ß-carotene/linoleic acid bleaching test, respectively.

Glabridin Prevents Doxorubicin-Induced Cardiotoxicity Through Gut Microbiota Modulation and Colonic Macrophage Polarization in Mice.

The chemotherapeutic drug doxorubicin (DOX) provokes a dose-related cardiotoxicity. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrated that glabridin (GLA), an isoflavone from licorice root, prevents DOX-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice. GLA reduced DOX-induced leakage of myocardial enzymes including aminotransferase, creatine kinase, lactate dehydrogenase, and creatine kinase-MB. GLA downregulated pro-apoptotic proteins (Bax, cleaved-caspase 9 and cleaved-caspase 3) and upregulated anti-apoptotic proteins (HAX-1 and Bcl-2) in the cardiac tissues. In addition, GLA modulated DOX-induced dysbiosis of gut microbiota and thereby decreased the ratio of M1/M2 colonic macrophage, accompanied by the downregulated lipopolysaccharide (LPS) and upregulated butyrate in the feces and peripheral blood. The leakage of myocardial enzymes induced by the DOX was decreased by antibiotics treatment, but not altered by co-treatment with the GLA and antibiotics. The ratio of M1/M2 colonic macrophage and leakage of myocardial enzymes reduced by the GLA were greatly increased by the Desulfovibrio vulgaris or LPS but decreased by the butyrate. Depletion of the macrophage attenuated DOX-induced cardiotoxicity but failed to further affect the effects of GLA. Importantly, GLA decreased production of M1 cytokines (IL-1ß and TNF-α) but increased production of M2 cytokines (IL-10 and TGF-ß) in the colonic macrophage with the downregulation of NF-κB and the upregulation of STAT6. In summary, GLA prevents DOX-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization, and may serve as a potential therapeutic strategy for the DOX-induced cardiotoxicity.