Haiying Zhu

The regenerative capacity of the liver is frequently insufficient following severe injury, and effective therapeutic strategies remain limited. Here, we identify CRX-527, a TLR4 agonist, as a novel inducer of hepatocyte proliferation in both healthy mice and a model of acetaminophen (APAP)-induced acute liver injury. Immunofluorescence analysis revealed that CRX-527-induced proliferative activity was predominantly observed in zone 2. Mechanistically, CRX-527 acts via TLR4 to induce transient IL-6 secretion, which subsequently activates the JAK2/STAT3 signaling pathway. In addition, metabolomic profiling identified taurochenodeoxycholic acid (TCDCA) as a synergistic partner of IL-6 in promoting hepatocyte proliferation. In APAP-injured mice, treatment with CRX-527 alone or in combination with IL-6 and TCDCA significantly reduced hepatic necrosis, accelerated tissue repair, and improved survival. Collectively, our findings uncover a previously unrecognized combined effect between IL-6/JAK2/STAT3 signaling and TCDCA in promoting hepatocyte proliferation and highlight CRX-527 and the IL-6/TCDCA combination as potential regenerative targets that warrant further preclinical evaluation for drug-induced liver injury, particularly in the setting of APAP overdose.

Inflammatory bowel disease (IBD) is sustained not only by dysregulated adaptive immunity, but also by profound disruption of the intestinal macrophage compartment. In healthy mucosa, macrophages maintain immune tolerance, support epithelial integrity, and coordinate repair. In IBD, however, these cells are reprogrammed into heterogeneous pathogenic states shaped by excessive monocyte recruitment, failed acquisition of resident programs, transcriptional and epitranscriptomic rewiring, metabolic stress, and persistent microenvironmental instruction. Macrophage behavior is continuously tuned by microbiota-derived metabolites, dietary signals, and reciprocal crosstalk with epithelial, stromal, and immune cells, placing macrophages at the center of a dynamic inflammatory circuit rather than at the end of a linear effector pathway. This review summarizes how macrophage dysregulation drives core pathological features of IBD, including cytokine amplification, defective microbial handling, epithelial barrier breakdown, fibrosis, and impaired mucosal healing. We further outline the current macrophage-directed therapeutic strategies, including targeted nanomedicine, metabolic reprogramming, biomimetic delivery systems, and vesicle- or gene-based approaches. Although these strategies remain constrained by lesion heterogeneity, incomplete human validation, and translational uncertainty, a more precise understanding of macrophage state architecture may provide a foundation for mechanism-based stratification and precision therapy in IBD.

Human atherosclerosis is increasingly recognized as a spatially organized inflammatory disease in which macrophages act as central regulators of lesion evolution rather than as a uniform foam-cell population. Recent single-cell and spatial profiling studies have redefined plaque macrophages as reproducible state programs, including inflammatory, interferon-responsive, lipid-associated, foamy, resident-like, and reparative phenotypes, each embedded within distinct microanatomic niches and multicellular communication networks. These programs are not merely descriptive, but are linked to clinically relevant features such as symptomatic disease, necrotic core expansion, fibrous cap thinning, extracellular matrix remodeling, and recurrent vascular risk. At the same time, the field remains limited by heterogeneity in plaque procurement, anatomic annotation, computational integration, and state nomenclature, which complicates cross-study comparison and obscures biological concordance. This review summarizes the recent advances in human plaque single-cell, spatial transcriptomic, and integrative multi-omics studies to outline the emerging architecture of macrophage states in atherosclerosis. We examine how atlas-scale frameworks connect state definition with spatial localization, regulatory circuitry, and lesion behavior, and discuss how these insights refine mechanistic understanding of plaque progression. We further highlight the translational potential of macrophage-state signatures for risk stratification, molecular imaging, and therapeutic targeting. A coherent human plaque macrophage atlas offers a conceptual and practical framework for moving from descriptive heterogeneity toward clinically actionable biology in atherosclerotic disease.

Targeting the dysregulation of essential metal homeostasis represents a rapidly evolving frontier in cancer immunotherapy. The tumor microenvironment (TME) is a complex immunosuppressive ecosystem comprising tumor cells, immune cells, stromal components, extracellular matrix, and diverse cytokines/chemokines, characterized by hypoxia, acidosis, elevated redox stress, and metabolic dysregulation that drive tumor progression and immunotherapy resistance. Crucially, dysregulated homeostasis of essential metals (e.g., Cu, Fe, Zn, Mg, Mn, Ca, Cr, Na, K) pervades the TME, directly promoting tumorigenesis through oncogenic pathway activation and aberrant energy metabolism while facilitating immune evasion, amplifying immunosuppression, and undermining cancer immunotherapies. In response, recent strategies have focused on leveraging metalloimmunology to reprogram the TME via: (1) activation of innate/adaptive immunity, (2) disruption of tumor metabolism, (3) induction of programmed cell death, and (4) triggering of immunogenic cell death (ICD). These approaches synergize with existing immunotherapies to enhance efficacy, aided by nanotechnology-enabled precision delivery of metal-based agents. In conclusion, by mastering the intricate interplay between metal ions and the immunosuppressive TME, these strategies hold immense potential to remodel the TME, reinvigorate anti-tumor immunity, and ultimately enhance the efficacy of next-generation cancer immunotherapies. This review presents metalloimmunology as an integrative paradigm connecting metal biology, tumor immunology, and nanotechnology, providing a transformative outlook for immunotherapy.

Background: Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood. Methods: Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation (macrophage 4) via an intermediate “stem–endothelial–monocyte" cell state. Integrated gene regulatory network inference and in silico perturbation modeling identified interferon regulatory factor 7 (IRF7) as a master transcriptional regulator orchestrating this specific pathogenic transition. Results: Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. In vivo, ApoE−/− mice challenged with a high-fat diet exhibited robust upregulation of IRF7 in aortic plaques, which co-localized with macrophage markers. Crucially, SMC-specific knockdown of Irf7 using an AAV-SM22α-shIRF7 vector significantly attenuated atherosclerotic plaque progression, reduced necrotic core formation, and enhanced fibrous cap stability. Mechanistically, Irf7 silencing preserved the contractile SMC phenotype and inhibited the accumulation of pro-inflammatory SMC-derived macrophage-like cells within the lesion. Conclusions: These findings identify IRF7 as a critical checkpoint in maladaptive SMC phenotype switching. We demonstrate that IRF7 drives the transdifferentiation of SMCs into a pro-inflammatory macrophage-like state, thereby fueling plaque instability. Consequently, therapeutic strategies capable of inhibiting IRF7-mediated SMC plasticity may prove effective in stabilizing vulnerable atherosclerotic plaques.

Background: Induced hepatic stem cells (iHepSCs) with the capacities of self-renewal and bidifferentiation into hepatocytes and cholangiocytes were generated from mouse embryonic fibroblasts (MEFs) by lineage reprogramming in our previous research. However, the mechanism of iHepSC self-renewal has not been elucidated. Active demethylation regulated by Tet1 plays an important role in the self-renewal of stem cells, including pluripotent stem cells and adult stem cells. Here, we investigated the role and mechanism of Tet1-regulated demethylation in the self-renewal of iHepSCs.Methods: The methylation levels and the expression of Tet1 in iHepSCs and MEFs were analyzed by immunofluorescent staining, quantitative reverse transcription PCR and western blotting. Then, the effects of Tet1 knockdown on the proliferation and self-renewal of iHepSCs were analyzed by CCK8, colony formation, and sphere formation assays. The mechanism by which Tet1 regulates the self-renewal of iHepSCs was investigated by chromatin immunoprecipitation, bisulfite sequence PCR, and methylation-sensitive restriction endonuclease-PCR.Results: The high level of 5hmC and the low level of 5mC in iHepSCs were accompanied by high expression of Tet1. After Tet1 expression was knocked down by shRNA in iHepSCs, the proliferation and self-renewal capacities were inhibited, and the expression of Myc was also decreased. The higher expression level of Myc in iHepSCs maintained its self-renewal and was regulated by Tet1, which directly binds to CBS-1 and site A regions of the Myc promoter and demethylates the CpG cytosine. In addition, CTCF also binds to the CBS-1 and site A regions of the Myc promoter and regulates Myc expression along with TET1.Conclusion: The self-renewal of iHepSCs was maintained by the higher expression of Myc, which was coregulated by TET1 and CTCF. This study may provide new insights into the self-renewal of stem cells, which can promote the research and application of ‘reprogrammed’ stem cells.

In 2006, Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4, Sox2, Klf44, and c-Myc. Since then, the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine. Of note, considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research. However, tumorigenicity, immunogenicity, and heterogeneity may hamper attempts to deploy this technology therapeutically. This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and how to assess the safety of induced pluripotent stem cells cell therapy products.

Evidence from clinical cases indicates an association between the low success rate of in vitro fertilization (IVF) and ovarian injury due to previous methotrexate (MTX) administration. Therefore, it is necessary to develop and propose reasonable clinical drug guidelines to improve the quality of oocytes and the development of embryos before pregnancy. In this study, we established a mouse model with previous MTX exposure to validate the effects of MTX on reproductive function in female mice. We observed that MTX administration could result in a decrease in the success rate of fertilization and an aberrant embryonic development in both natural fertilization and IVF, even after completion of five to six ovulation cycles after MTX withdrawal. Further research revealed senescence and apoptosis of follicular granulosa cells (GCs), accompanied by arrested follicle development and aberrant estradiol and anti‐Mullerian hormone levels. Supportive evidence indicated that MTX administration induced senescence and apoptosis of human GCs in vitro, and the effects were consistent with the high levels of p21, p53, and oxidative stress. We further demonstrated that folic acid (FA) could improve oocyte function and embryonic development in vivo and in vitro by protecting GCs against apoptosis and senescence. Based on these findings, we propose the implementation of extended intervals between MTX exposure and conception or IVF and recommend FA as a special dietary supplement during this interval period; however, prospective inquiry in humans is necessary to further understand the relationship between MTX and FA recovery.

Recent studies have shown that metal and metal oxide have a potential function in anti-tumor therapy. Our previous studies demonstrated that cuprous oxide nanoparticles (CONPs) not only selectively induce apoptosis of tumor cells in vitro but also inhibit the growth and metastasis of melanoma by targeting mitochondria with little hepatic and renal toxicities in mice. As a further study, our current research revealed that CONPs induced apoptosis of human melanoma stem cells (CD271^+/high cells) in A375 and WM266-4 melanoma cell lines and could significantly suppress the expression of MITF, SOX10 and CD271 involved in the stemness maintenance and tumorigenesis of melanoma stem cells. CD271^+/high cells could accumulate more CONPs than CD271^-/low through clathrin-mediated endocytosis. In addition, lower dosage of CONPs exhibited good anti-melanoma effect by decreasing the cell viability, stemness and tumorigenesis of A375 and WM266-4 cells through reducing the expression of SOX10, MITF, CD271 and genes in MAPK pathway involved in tumor progression. Finally, CONPs obviously suppressed the growth of human melanoma in tumor-bearing nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice, accompanied with tumors structural necrosis and fibrosis remarkably and decreased expression of CD271, SOX10 and MITF. These results above proved the effectiveness of CONPs in inhibiting melanoma progress through multiple pathways, especially through targeting melanoma stem cells.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Zhengyu Jiang1, 2, 3, Hongxia Zhang1, 2, Ye Wang1, 2, Bin Yu1, 2, Chen Wang1, 2, Changcheng Liu1, 2, Juan Lu4, Fei Chen1, 2, Minjun Wang1, 2, Xinlu Yu1, 2, Jiahao Lin5, Xinghua Pan6, Pin Wang7, Haiying Zhu1, 2 1Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China 2Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, P.R. China 3Department of Anesthesiology, Second Military Medical University, Shanghai, P.R. China 4Training Department, Second Military Medical University, Shanghai, P.R. China 5School of Clinic Medicine, Second Military Medical University, Shanghai, P.R. China 6Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 7National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, P.R. China Correspondence to: Pin Wang, e-mail: pinqi21sh@163.com Haiying Zhu, e-mail: hyzhu@smmu.edu.cn Keywords: cancer immunotherapy, DMSO, anti-tumor immunity Received: July 14, 2015 Accepted: January 01, 2016 Published: January 25, 2016 ABSTRACT Cancer immunotherapy is the use of the immune system to treat cancer. Our current research proposed an optional strategy of activating immune system involving in cancer immunotherapy. When being treated with 2% DMSO in culture medium, Hepa1-6 cells showed depressed proliferation with no significant apoptosis or decreased viability. D-hep cells, Hepa1-6 cells treated with DMSO for 7 days, could restore to the higher proliferation rate in DMSO-free medium, but alteration of gene expression profile was irreversible. Interestingly, tumors from D-hep cells, not Hepa1-6 cells, regressed in wild-type C57BL/6 mice whereas D-hep cells exhibited similar tumorigenesis as Hep1–6 cells in immunodeficient mice. As expected, additional Hepa1-6 cells failed to form tumors in the D-hep-C57 mice in which D-hep cells were eliminated. Further research confirmed that D-hep-C57 mice established anti-tumor immunity against Hepa1-6 cells. Our research proposed viable tumor cells with altered biological features by DMSO-treatment could induce anti-tumor immunity in vivo.