Hepatocellular carcinoma (HCC) stands as one of the most lethal cancers globally, with its treatment constrained by limitations of conventional therapies. In this study, we developed zinc-doped Salvia miltiorrhiza-derived carbon dots (Zn-SaCDs) and encapsulated them within apoptotic bodies (Zn-SaCDs@Ap) to induce targeted, broad-spectrum cell death in hepatocellular carcinoma (HCC). In vitro experiments reveal that Zn-SaCDs@Ap effectively inhibits stemness properties and invasive potential while triggering robust apoptosis in HCC cells. Furthermore, studies on orthotopic liver tumors and subcutaneous tumors in mice showed that Zn-SaCDs@Ap can effectively inhibit tumor growth. It is noteworthy that Zn-SaCDs@Ap can induce various types of cell death, including apoptosis, pyroptosis, and necroptosis. Transcriptome analysis reveals that Zn-SaCDs@Ap treatment markedly activates the expression of the C2H2 zinc finger family transcription factors (KLF7, SALL4, SNAI2, ZNF516), which enhance the expression of key proteins involved in PANoptosis regulation, such as AIM2 and NAIP. In conclusion, Zn-SaCDs@Ap can inhibit the progression of HCC though inducing PANoptosis of tumor cells. Zn-SaCDs@Ap demonstrates potential as a novel therapeutic agent for hepatocellular carcinoma (HCC).

Zinc finger protein 750 (ZNF750) is a novel tumor suppressor in esophageal squamous cell carcinoma (ESCC). However, its role in metabolic remodeling in ESCC remains unclear. Single-cell RNA sequencing data (GSE160269) from 66 ESCC samples indicated that ZNF750 was specifically expressed in epithelial cells and was associated with lipid metabolic pathways in ESCC. Lipidomic assays demonstrated that ZNF750 deficiency induced lipid metabolic reprogramming, especially polyunsaturated fatty acid (PUFA) remodeling, and significantly enhanced ESCC cell membrane fluidity and promoted malignant phenotypes. Further transcriptomic analysis indicated that ZNF750-associated genes were enriched in pathways related to PUFA metabolism. Mechanistically, ZNF750 binds to the promoter of fatty acid desaturase 1 (FADS1) to inhibit its transcription and expression, thereby modulating lipid saturation and ultimately impacting ESCC cell phenotypes. Furthermore, ZNF750 knockdown significantly enhanced the ferroptosis sensitivity of ESCC cells through transcriptional regulation of acyl-CoA synthetase long-chain family member 4 (ACSL4). Overall, our study delineates the lipidomic landscape regulated by ZNF750 and elucidates its dual role in modulating PUFA metabolism and ferroptosis sensitivity. These findings suggest that targeting PUFA metabolism and ferroptosis are potential therapeutic strategies for ESCC patients with ZNF750 mutations or deletions.

Ginsenoside Rh2 (G-Rh2) is a primary bioactive constituent of ginseng (Panax ginseng C.A. Meyer), has been demonstrated to possess anti-tumor potential. However, its specific inhibitory effects on triple-negative breast cancer (TNBC) and the associated molecular mechanisms have not been fully elucidated. The hypoxic microenvironment is a key factor driving TNBC malignancy and dissemination, often leading to enhanced tumor invasiveness and increased metastatic risk. This study aimed to evaluate the inhibitory effects of G-Rh2 on TNBC cells and tumor growth and to identify the key molecular mechanisms responsible. This study integrated multiple experimental techniques, including western blot, immunofluorescence, histopathological staining, co-immunoprecipitation, cellular thermal shift assay, cell scratch assay, and molecular docking. Additionally, network pharmacology, hypoxia inducible factor 1α (HIF-1α) overexpression validation, and HIF-1α small interfering RNA (si-RNA)-mediated knockdown were combined to systematically dissect its key regulatory pathways. G-Rh2 was shown to suppress the growth of breast tumors in mice and concurrently induce apoptosis in TNBC cells. The underlying mechanisms involved downregulation of HIF-1α expression, activation of the Hippo pathway to suppress cell migration and invasion, and intervention in the HIF-1α/YAP nuclear translocation axis, thereby inhibiting epithelial mesenchymal transition (EMT). This study systematically revealed the inhibitory effect of G-Rh2 on TNBC through in vivo and in vitro models, providing new mechanistic evidence and theoretical support for natural product-based antitumor research.

Highly aggressive tumor cells fulfill their metabolic demands by forming vascular-like channels through a process of cellular deformation and extracellular matrix (ECM) remodeling, known as vasculogenic mimicry (VM). This phenomenon contributes to the limited efficacy of anti-angiogenic therapies and promotes tumor progression, making VM inhibition a promising yet challenging therapeutic strategy. To address this, we developed a biomimetic nanoplatform, termed GDVs@CuPBA-iRGD, through the in-situ mineralization of a copper-based Prussian blue analogue (CuPBA) onto ginseng-derived vesicles (GDVs), followed by conjugation with the tumor-penetrating peptide iRGD. The resulting nanocomposite exhibited excellent pH-responsive degradation, enabling controlled drug release within the tumor microenvironment. In vitro, GDVs@CuPBA-iRGD was efficiently internalized by hepatocellular carcinoma (HCC) cells, significantly suppressing their viability, invasion, and VM formation while simultaneously inducing cuproptosis and ferroptosis. Consistent with these findings, in vivo studies confirmed that GDVs@CuPBA-iRGD exhibits superior accumulation in the liver, resulting in potent inhibition of both VM and tumor progression, all while maintaining high biosafety. Mechanistically, the anti-VM effect is primarily mediated by the nuclear translocation of PPARγ. This key event triggers a transcriptional reprogramming that downregulates critical VM-associated genes, thereby disrupting the ECM remodeling essential for VM. Moreover, single-cell RNA sequencing (scRNA-seq) analysis indicated that VM suppression by GDVs@CuPBA-iRGD triggered the subsequent activation of antitumor immunity. This work highlights a novel bioinspired and synergistic therapeutic strategy for the precise treatment of VM-dependent aggressive tumors.

The carcinogenesis and progression of hepatocellular carcinoma (HCC) are closely related to viral infection and intestinal bacteria. However, little is known about bacteria within the HCC tumor microenvironment. Here, we showed that intratumoral Mycoplasma hyorhinis (M. hyorhinis) promoted the initiation and progression of HCC by enhancing nuclear ploidy. We quantified M. hyorhinis in clinical tissue specimens of HCC and observed that patients with high M. hyorhinis load had poor prognosis. We found that gastrointestinal M. hyorhinis can retrogradely infect the liver through the oral-duodenal-hepatopancreatic ampulla route. We further found that the increases in mononuclear polyploidy and cancer stemness resulted from mitochondrial fission caused by intracellular M. hyorhinis. Mechanistically, M. hyorhinis infection promoted the decay of mitochondrial fusion protein (MFN) 1 mRNA in an m6A-dependent manner. Our findings indicated that M. hyorhinis infection promoted pathological polyploidization and suggested that Mycoplasma clearance with antibiotics or regulating mitochondrial dynamics might have the potential for HCC therapy.

Sepsis is a life-threatening disease caused by a dysregulated immune response to infection, often involving the translocation of Gram-negative bacteria such as Escherichia coli (E. coli) into the bloodstream, triggering a cytokine storm. Despite its severity, no effective drugs currently exist for sepsis treatment. This study explores whether pathogen-derived carbon dots can mitigate their inherent toxicity while leveraging their structural similarity to pathogens to competitively bind pattern recognition receptors, thereby inhibiting sepsis. Based on this concept, E. coli wall-derived carbon dots (E-CDs) are synthesized and shown to reduce inflammatory cytokine production, protect organ function, and improve survival in septic mice. Mechanistic studies reveal that E-CDs competitively bind to lipopolysaccharide-binding protein with lipopolysaccharide, promoting toll-like receptor 4 degradation via the lysosomal pathway and inhibiting nuclear factor kappa-B (NF-κB) activation. Additionally, E-CDs exhibit antioxidant properties, reducing oxidative stress and mitochondrial DNA release, thereby suppressing overactivation of the stimulator of interferon genes pathway. In septic cynomolgus monkeys and patient-derived peripheral blood mononuclear cells, E-CDs alleviate inflammation and oxidative stress. Overall, this study demonstrates that E-CDs can suppress the cytokine storm in sepsis by co-silencing innate immune pathways, suggesting that converting pathogens into carbon dots offers a novel therapeutic strategy.

This study investigates the role of advanced glycation end-products (AGEs) in tumor vasculogenic mimicry (VM). Using high-sugar diet animal models and glycated extracellular matrix (ECM) ex vivo models, AGEs derived is demonstrated from glycated ECM significantly enhanced tumor growth and VM formation. However, carbon dots (egCDs) derived from glycated ECM effectively inhibit tumor growth and VM formation in this glycated microenvironment. Mechanistic studies show that AGEs from glycated ECM bind to the Receptor of Advanced Glycation Endproducts (RAGE) receptors on tumor cells, promoting RAGE nuclear translocation and binding with high mobility group box 1 (HMGB1), which increases the transcription of Snail family transcriptional repressor 2 (SNAI2), thereby driving VM formation. However, egCDs competitively bind to RAGE, promoting its lysosomal degradation and blocking VM formation induced by the RAGE-HMGB1-SNAI2 axis. In conclusion, this study demonstrates that egCDs can target RAGE and promote its lysosomal degradation to block VM formation induced by glycated ECM. This finding not only reveals the transformation of glycated ECM from a pro-VM factor to an anti-VM therapeutic agent after carbonization, but also provides a theoretical basis for the innovative strategy of "reconstructing pathogenic substances into carbon dots to reverse disease-driving factors into therapeutic targeting carriers".

Myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME) contribute to the malignant progression of tumors by exerting immunosuppressive effects. Bacterial lipopolysaccharides (LPS) have been widely demonstrated in various types of solid tumors. LPS can promote the malignant progression of tumors, which mechanism has not yet been fully elucidated. In this study, a type of MDSC-like tumor cells (MLTCs) is found in tumor tissues induced by low-dose and long-term LPS stimulation. MLTCs can simultaneously express tumor cell and MDSCs markers. Similar to MDSCs, MLTCs can produce arginine, nitric oxide, and reactive oxygen species and inhibit the activity of NK and T cells to promote the formation of an immunosuppressive microenvironment. MLTCs can also promote tumor cell proliferation and vasculogenic mimicry formation. CRISPR-Cas9 activity screening studies identified RNA-binding Fox-1 homolog 3 (Rbfox3) as a critical protein for MLTCs formation after LPS treatment. Rbfox3 can transcriptionally regulate the expression of Ass1 in the form of phase-separated particles. Crocin can inhibit the generation of MLTCs by disrupting phase-separated particles of Rbfox3 and enhance the anti-tumor effects of immune checkpoint inhibitors (ICIs).

Background Myeloid-derived suppressor cells (MDSCs) promote tumor growth, metastasis, and lead to immunotherapy resistance. Studies revealed that miRNAs are also expressed in MDSCs and promote the immunosuppressive function of MDSCs. Currently, few studies have been reported on inducible cellular microvesicle delivery of nucleic acid drugs targeting miRNA in MDSCs for the treatment of malignant tumors.Results and conclusion In this study, we designed an artificial DNA named G-quadruplex-enhanced circular single-stranded DNA-9 (G4-CSSD9), that specifically adsorbs the miR-9 sequence. Its advanced DNA folding structure, rich in tandem repeat guanine (G-quadruplex), also provides good stability. Mesenchymal stem cells (MSCs) were prepared into nanostructured vesicles by membrane extrusion. The MSC microvesicles-encapsulated G4-CSSD9 (MVs@G4-CSSD9) was delivered into MDSCs, which affected the downstream transcription and translation process, and reduced the immunosuppressive function of MDSCs, so as to achieve the purpose of treating melanoma. In particular, it provides an idea for the malignant tumor treatment.

Background Enhancing immunogenicity and antigen-presentation efficiency is critical for tumor vaccine development. While yeast-surface glycoprotein side chains can improve antigen presentation, their ability to deliver tumor antigens remains limited.Methods The composite carbon nanopolymers (Asparagine-N-acetylglucosamine-Mannose derived carbon nanopolymers, ANM-NPs) mimicking yeast-surface glycans side chains were prepared using asparagine, N-acetylglucosamine and mannose as precursors via microwave-assisted synthesis method. Combined with whole-cell tumor antigen (T-Ag), the vaccine ANM-NPs@T-Ag was prepared. The expression levels of major histocompatibility complex-II, CD80, and CD86 were analyzed by flow cytometry to evaluate the enhancement of antigen presentation. The antitumor efficacy of ANM-NPs@T-Ag was assessed by H22-LUC and B16-F10-LUC tumor-bearing models.Results ANM-NPs have an average particle size of approximately 21.69 nm and exhibit good stability. Compared with traditional aluminum adjuvants, ANM-NPs demonstrate superior efficacy in promoting antigen presentation and immune activation. ANM-NPs effectively stimulated innate immunity, facilitated immune cell infiltration, and enhanced adaptive immune responses. The vaccine ANM-NPs@T-Ag targeted dendritic cells via mannose receptors, activating the lectin pathway, improving complement opsonization, and enhancing antigen presentation. ANM-NPs@T-Ag stimulated cellular/humoral immunity, increased tumor-specific IgG, and inhibited tumor growth. ANM-NPs@T-Ag also enhanced the antitumor effect of α-PD-1 (programmed cell death protein-1).Conclusion These findings demonstrate that ANM-NPs can serve as a potential vaccine adjuvant, and ANM-NPs@T-Ag represents a promising tumor vaccine candidate.Cite Now

Receptor for advanced glycation end products (RAGE) plays an important role in skin glycation damage. High-mobility group 1B protein (HMGB1) and advanced glycation end products (AGEs) are key RAGE ligands. Simultaneous inhibition of HMGB1/RAGE and AGEs/RAGE pathways maybe an effective strategy to alleviate glycation induced skin damage. In this work, Theasinensin A (TSA) is identified as the active molecule inhibiting HMGB1-RAGE interaction through molecular docking. To simultaneously suppress HMGB1/RAGE and AGEs/RAGE pathways, Zn-based multi-active framework nanoparticles TSA-CAN-Zn are designed, which contain TSA and the active molecule L-carnosine (CAN) that inhibits AGEs production. In vitro studies demonstrated that TSA-CAN-Zn have radical scavenging activity and AGEs formation inhibition activity. TSA-CAN-Zn can not only inhibit ROS accumulation, cell apoptosis, and inflammatory factors production induced by glycation in HaCaT cells but also enhanced the lysosomal degradation of AGEs. TSA-CAN-Zn also mitigated the damage caused by glycation in mouse skin glycation model. Single-cell RNA sequencing results revealed the impact of TSA-CAN-Zn on different cell types of skin tissue, especially the basal cells of the epidermal layer and inflammation-related macrophages. And pathway analysis revealed that TSA-CAN-Zn mainly influences the downstream pathways of RAGE. Collectively, TSA-CAN-Zn is a promising therapeutic candidate for ameliorating glycation-induced skin damage.

Rationale: Tumor cells are ideal candidates for developing cancer vaccines due to their antigenic profiles, yet existing whole-cell vaccines lack efficacy. This study aimed to develop a novel whole-cell vaccine platform that combines immunogenicity, structural integrity, and tumor-targeting capabilities. Methods: We created "Magnetic Sculpture-like (MASK) Cells" by treating tumor cells with high-concentration FeCl3, inducing rapid morphological fixation without traditional chemical crosslinking. MASK cells were characterized for proliferative capacity, biomolecule retention, and magnetic properties. Vaccine efficacy was tested in vitro, in melanoma-bearing mouse models, and through spatial transcriptomic profiling of tumor microenvironments. Combination therapy with anti-PD-1 was further evaluated. Results: MASK cells lose proliferative ability but retain biomolecules and architecture. MASK cells promote dendritic cell maturation and T cell responses against tumors. Vaccines combining MASK cells and adjuvant potently suppress melanoma growth. Uniquely, FeCl3 sculpting imparts magnetism to cells, enabling directional navigation to tumors using magnetic fields and enhanced in situ immune activation. Spatial transcriptomics reveals DC and T cell activation and tumor cytotoxicity after MASK vaccination. Combined with anti-PD-1, MASK cell vaccines strongly inhibit growth and improve survival. Conclusion: MASK cells represent a promising new approach for targeted, patient-specific anti-tumor therapeutics.

Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with poor prognosis and high incidence. The clinical data analysis of liver hepatocellular carcinoma samples downloaded from The Cancer Genome Atlas reveals that the THO Complex 1 (THOC1) is remarkable upregulated in HCC and associated with poor prognosis. However, the underlying mechanism remains to be elucidated. We hypothesize that THOC1 can promote the proliferation of HCC. The present study aims to identify THOC1 as the target for HCC treatment and broaden our sights into therapeutic strategy for this disease. Methods Quantitative RT-PCR, Western blot, immunofluorescence and immunohistochemistry were used to measure gene and protein expression. Colony formation and cell cycle analysis were performed to evaluate the proliferation. The gene set enrichment analysis were performed to identify the function which THOC1 was involved in. The effects of THOC1 on the malignant phenotypes of hepatocellular cells were examined in vitro and in vivo. Results The gene set enrichment analysis reveals that THOC1 can promote the proliferation and G2/M cell cycle transition of HCC. Similarly, experimental results demonstrate that THOC1 promotes HCC cell proliferation and cell cycle progression. The knockdown of THOC1 leads to R-loop formation and DNA damage and confers sensitivity to cisplatin. In addition, in vivo data demonstrate that THOC1 can enhance tumorigenesis by increasing tumor cell proliferation. Furthermore, virtual screening predicts that THOC1 as a direct target of luteolin. Luteolin can induce DNA damage and suppress the proliferation of HCC by targeting THOC1. Furthermore, the inhibition of THOC1 activity by luteolin enhances the chemosensitivity of HCC tumor cells to cisplatin. Conclusions THOC1 was identified as a predictive biomarker vital for HCC-targeted treatments and improvement of clinical prognosis. Luteolin combined with cisplatin can effectively suppress HCC tumor growth, indicating a potential and effective therapeutic strategy that uses luteolin in combination with conventional cytotoxic agents for HCC treatment.

Background and Purpose: Long-term Ultraviolet (UV) exposure can cause inflammation, pigmentation, and photoaging damage.Retinoic acid drugs are commonly used RAR agonists in the clinical treatment of UV-induced skin problems, but the use of such drugs is often accompanied by some systemic adverse reactions caused by nonspecific activation of RARs. Therefore, this study is expected to screen a novel RAR-γ selective agonist with high safety Experimental Approach: Molecular docking, dynamic simulation and Biacore were used to screen and obtain a novel RAR- γ selective agonists. RT‐PCR , ELISA, western blot, immunofluorescence staining, flow cytometry and proteome analysis were used to detect the effects of novel RAR-γ selective agonists on UV-induced inflammation and photoaging cell model. UV-induced mouse models and volunteer skin tests were used to evaluate the effects of TEC on skin repair, aging and inflammation. Key Results: TEC is a novel RAR-γ selective agonist. TEC can inhibit UV-induced oxidative damage, inflammatory factor release, and MMPs production. TEC can also reverse the loss of collagen induced by UV. The results of signaling pathway research showed that TEC mainly affect the MAPK/JNK/AP-1 pathway. Nanoparticle-loaded TEC, which significantly improved the effect of TEC, was also presented. TEC can reduce inflammation areas and facial wrinkles and caused less skin irritation than tretinoid (TRE). Conclusions and Implications: TEC is a non-retinol RAR-γ selective agonist, which can inhibit UV-induced skin damage and may be developed as a safe pharmaceutical component for the prevention of photoaging and skin inflammation.

Abstract Oleanolic acid exhibits extensive pharmacologic activities and takes significant antitumor effects. Its pharmacologic mechanism, however, still remained to be further clarified. In this study, we demonstrated that oleanolic acid attenuated the migration and invasion abilities, resulting in the suppression of the epithelial–mesenchymal transition (EMT) process in liver cancer cells, and inhibited the tumor growth of the peritoneal lymphocytes–bearing mice. We further proved that inducible nitric oxide synthase (iNOS) may be the potential target of oleanolic acid. We confirmed that oleanolic acid could promote the dimerization of iNOS, activating it, and subsequently increasing the production of nitric oxide. Further experiments indicated that oleanolic acid promoted the nitration of specific proteins and consequently suppressed their EMT-related biological functions. Furthermore, it has been confirmed that oleanolic acid enhanced the antitumor effects of regorafenib in liver cancer treatment. These results deepened our understanding of the pharmacologic mechanism of the antitumor effect oleanolic acid, and the importance of nitric oxide synthetase as a therapeutic target for liver cancer treatment.