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Ferroptosis represents a form of programmed cell death that is propelled by iron-dependent lipid peroxidation, thereby being distinguished by the prominent features of iron accumulation and lipid peroxidation. Ferroptosis has been implicated in numerous physiological and pathological phenomena, with mounting indications that it holds significant implications for cancer and other medical conditions. On one side, it demonstrates anti-cancer properties by triggering ferroptosis within malignant cells, and on the other hand, it damages normal cells causing other diseases. Therefore, in this paper, we propose to review the paradoxical regulation of ferroptosis in tumors and other diseases. First, we introduce the development history, concept and mechanism of ferroptosis. The second part focuses on the methods of inducing ferroptosis in tumors. The third section emphasizes the utilization of ferroptosis in different medical conditions and strategies to inhibit ferroptosis. The fourth part elucidates the key contradictions in the control of ferroptosis. Finally, potential research avenues in associated domains are suggested.

Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe 3+ and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe 3+ and TA. Fe 3+ is reduced to Fe 2+ by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.

Nanocarriers have therapeutic potential to facilitate drug delivery, including biological agents, small-molecule drugs, and nucleic acids. However, their efficiency is limited by several factors; among which, endosomal/lysosomal degradation after endocytosis is the most important. This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms. These strategies include promoting endosomal/lysosomal escape, using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes. On the basis of the findings of this review, we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.

Conventional cancer treatments often have complications and serious side effects, with limited improvements in 5-year survival and quality of life. Photothermal therapy (PTT) employs materials that convert light to heat when exposed to near-infrared light to raise the temperature of the tumor site to directly ablate tumor cells, induce immunogenic cell death, and improve the tumor microenvironment. This therapy has several benefits, including minimal invasiveness, high efficacy, reduced side effects, and robust targeting capabilities. Beyond just photothermal conversion materials, nanoplatforms significantly contribute to PTT by supplying effective photothermal conversion materials and bolstering tumor targeting to amplify anti-tumor effects. However, the anti-tumor effects of PTT alone are ultimately limited and often need to be combined with other therapies. This narrative review describes the recent progress of PTT combined with chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, gene therapy, gas therapy, chemodynamic therapy, photoacoustic imaging, starvation therapy, and multimodal therapy. Studies have shown that combining PTT with other treatments can improve efficacy, reduce side effects, and overcome drug resistance. Despite the encouraging results, challenges such as optimizing treatment protocols, addressing tumor heterogeneity, and overcoming biological barriers remain. This paper highlights the potential for personalized, multimodal approaches to improve cancer treatment outcomes.

Background Celastrol (cel) was one of the earliest isolated and identified chemical constituents of Tripterygium wilfordii Hook. f. Based on a cel probe (cel-p) that maintained the bioactivity of the parent compound, the targets of cel in cerebral ischemia–reperfusion (I/R) injury were comprehensively analyzed by a quantitative chemical proteomics method. Methods We constructed an oxygen–glucose deprivation (OGD) model in primary rat cortical neurons and a middle cerebral artery occlusion (MCAO) model in adult rats to detect the direct binding targets of cel in cerebral I/R. By combining various experimental methods, including tandem mass tag (TMT) labeling, mass spectrometry, and cellular thermal shift assay (CETSA), we revealed the targets to which cel directly bound to exert neuroprotective effects. Results We found that cel inhibited the proinflammatory activity of high mobility group protein 1 (HMGB1) by directly binding to it and then blocking the binding of HMGB1 to its inflammatory receptors in the microenvironment of ischemia and hypoxia. In addition, cel rescued neurons from OGD injury in vitro and decreased cerebral infarction in vivo by targeting HSP70 and NF-κB p65. Conclusion Cel exhibited neuroprotective and anti-inflammatory effects by targeting HSP70 and NF-κB p65 and directly binding to HMGB1 in cerebral I/R injury.

Background Endometriosis (EMs), the ectopic planting of functional endometrium outside of the uterus, is a leading cause of infertility and pelvic pain. As a fundamental mRNA modification, N6-methyladenosine (m6A) participates in various pathological processes. However, the role of m6A RNA modification in endometriosis remains unclear. The present study explores METTL3-mediated m6A modification and the mechanisms involved in endometriosis. Methods The dominant m6A regulators in EMs were analysed using RT‒PCR. Candidate targets and possible mechanisms of METTL3 were assessed by m6A-mRNA epitranscriptomic microarray and RNA sequencing. A primary ESCs model was employed to verify the effect of METTL3 on m6A modification of SIRT1 mRNA, and the mechanism was elucidated by RT‒PCR, Western blotting, MeRIP, and RIP assays. CCK-8 viability assays, Transwell invasion assays, EdU proliferation assays, wound healing migration assays, and senescence-associated β-galactosidase staining were performed to illuminate the potential biological mechanism of METTL3 and SIRT1 in ESCs in vitro. An in vivo PgrCre/ + METTL3 −/− female homozygous mouse model and a nude mouse xenograft model were employed to further investigate the physiologic consequences of METTL3-mediated m6A alteration on EMs. Results Our data show that decreased METTL3 expression significantly downregulates m6A RNA methylation levels in ESCs. Silencing m6A modifications mediated by METTL3 accelerates ESCs viability, proliferation, migration, and invasion in vitro. The m6A reader protein YTHDF2 binds to m6A modifications to induce the degradation of SIRT1 mRNA. SIRT1/FOXO3a signalling pathway activation is subsequently inhibited, promoting the cellular senescence of ESCs and inhibiting the ectopic implantation of ESCs in vitro and in vivo. Conclusions Our findings demonstrate that METTL3-mediated m6A methylation epigenetically regulates the ectopic implantation of ESCs, resulting in the progression of endometriosis. Our study establishes METTL3-YTHDF2-SIRT1/FOXO3a as a critical axis and potential mechanism in endometriosis.

Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the “best hope for the treatment of malaria” by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the “artemisinin story” and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.

Cellular senescence plays a critical role in repeated ultraviolet (UV) exposure‐induced skin photoaging. Currently, from the perspective of regulating senescent cells, potent compounds or reliable protein targets that could effectively prevent skin photoaging have not yet been reported. Herein, we demonstrated that chlorogenic acid (CGA) significantly inhibited UVA‐induced senescence of human dermis skin fibroblasts (HDF) cells by screening the natural product library. The activity‐based protein profiling (ABPP) result revealed that Enolase 1 (ENO1) is one of the direct targets of CGA in HDF cells. Further mechanism research indicated that CGA covalently binds to ENO1, and prevented UVA‐induced cellular senescence by suppressing the activity of ENO1 protein to block the glycolytic pathway. Importantly, we found that CGA dose‐dependently reduced the skin wrinkle score, alleviated skin pathological features and inhibited senescent characteristics in a photoaging mouse model. The proteomic analysis revealed that CGA treatment effectively inhibited senescence‐associated secretory phenotype (SASP) secretion and glycolysis in skin samples of mice. Collectively, our study not only demonstrated that inhibiting cell senescence is an effective anti‐skin photoaging strategy, but also revealed that ENO1 is a promising protein target to prevent photoaging. A schematic depiction of chlorogenic acid inhibited UVA‐induced cellular senescence and mouse skin photoaging by suppressing the activity of Enolase 1 (ENO1) protein to block glycolytic pathway.

Tissue‐resident memory T (TRM) cells are crucial components of the immune system that provide rapid, localized responses to recurrent pathogens at mucosal and epithelial barriers. Unlike circulating memory T cells, TRM cells are located within peripheral tissues, and they play vital roles in antiviral, antibacterial, and antitumor immunity. Their unique retention and activation mechanisms, including interactions with local epithelial cells and the expression of adhesion molecules, enable their persistence and immediate functionality in diverse tissues. Recent advances have revealed their important roles in chronic inflammation, autoimmunity, and cancer, illuminating both their protective and their pathogenic potential. This review synthesizes current knowledge on TRM cells’ molecular signatures, maintenance pathways, and functional dynamics across different tissues. We also explore the interactions of TRM cells with other immune cells, such as B cells, macrophages, and dendritic cells, highlighting the complex network that underpins the efficacy of TRM cells in immune surveillance and response. Understanding the nuanced regulation of TRM cells is essential for developing targeted therapeutic strategies, including vaccines and immunotherapies, to enhance their protective roles while mitigating adverse effects. Insights into TRM cells’ biology hold promise for innovative treatments for infectious diseases, cancer, and autoimmune conditions. Tissue‐resident memory T (TRM) cells are crucial components of the immune system and play vital roles in antiviral, antibacterial, and antitumor immunity, as well as chronic inflammation conditions and graft‐versus‐host diseases. Understanding the intricate regulation of TRM cells is crucial for developing targeted therapeutic strategies, such as vaccines and immunotherapies, that enhance their protective functions while minimizing potential adverse effects.

Population pharmacokinetic (PPK) model is capable of identifying the factors that influence the variability of pharmacokinetic (PK) profiles and the degree of their influence, effectively reduces unexplained variability, and demonstrates excellent predictive ability. PPK model has been successfully constructed in several populations for a variety of drugs. However, no study has yet conducted a bibliometric analysis of publications related to the PPK model. This study aims to provide a comprehensive overview of the research progress and hotspots in the field of PPK model research through bibliometric methods. A systematic search of the Web of Science database was conducted to collect articles and reviews related to the PPK model between 2000 and 2024. We then analyzed the data using Bibliometrix R package, Microsoft Office Excel, CiteSpace and VOSviewers. Between 2000 and 2024, we identified a total of 6,125 papers and 128,856 citations. The average annual growth rate of the relevant publications was 10.35%, showing continued growth momentum. These research outputs are concentrated in North America, Western Europe, and East Asia, with USA leading the way with 2,340 publications and having the highest H-index (93) and total citations (54,965). Uppsala University and are the institutions with the highest publication output and the most influential journals, respectively. Most of the funding agencies are from the USA and the subject categories for most publications are Pharmacology Pharmacy. In terms of author contributions, professor Karlsson MO is the leader in the field with 149 publications. In addition, wo found that \"critically ill patients,\" \"tacrolimus,\" \"machine learning,\" \"external evaluation,\" \"polymyxin b,\" \"voriconazole,\" \"extracorporeal membrane oxygenation,\" \"dose optimization\" and \"model-informed precision dosing\" are current research hotspots and future research trends. This study is the first comprehensive overview of the development of PPK model and research hotspots using bibliometric methods. Our findings provide researchers, especially beginners, with insights into the application area of PPK model, helping them to grasp key information in the field.