Medicinal Research Reviews最新文献

{"title":"Hepatotoxicity in the Era of Precision Medicine: Toxicological Mechanisms and Management of Immune and Cell Therapy-Induced Liver Injury.","authors":"Yujian Fan, Xiaokai Guo, Jiaying Lyu, Xinyu Wang, Fanjie Xu, Junzhen Yan, Yisheng He","doi":"10.1002/med.70093","DOIUrl":"https://doi.org/10.1002/med.70093","url":null,"abstract":"<p><p>Immune checkpoint inhibitors and adoptive cell therapies have revolutionized cancer treatment, yet their success is accompanied by immune-related hepatotoxicity that can range from asymptomatic enzyme elevation to life-threatening liver failure. Unlike conventional drug-induced liver injury, immune-mediated hepatotoxicity arises from complex, therapy-specific mechanisms that remain incompletely understood, creating critical knowledge gaps in risk prediction and prevention. This review incorporates current evidence on the clinical presentation, mechanistic pathways, and risk factors underlying hepatotoxicity across major immune and cell therapy platforms, with emphasis on translating mechanistic insights into actionable management strategies. We systematically examine hepatotoxicity patterns for immune checkpoint inhibitors, CAR-T cell therapies, bispecific T-cell engagers, and tumor-infiltrating lymphocyte therapy, integrating clinical trial data, real-world evidence, and mechanistic studies. Our analysis shows distinct injury mechanisms: T-cell-mediated hepatocyte destruction following checkpoint blockade, cytokine-driven bystander injury during cytokine release syndrome, and emerging on-target/off-tumor toxicity from engineered lymphocytes. Critical risk modifiers include pre-existing liver disease, concomitant hepatotoxic medications, gut microbiome dysbiosis from antibiotic exposure, and host pharmacogenomic variation. We propose three priority research directions: development of predictive biomarkers enabling pretreatment risk stratification, microbiome-directed interventions to preserve hepatic immune tolerance, and implementation of Safety-by-Design engineering strategies that integrate hepatotoxicity prevention into therapeutic design. This review provides a mechanistic framework for transitioning from reactive toxicity management to predictive, personalized prevention, essential for maximizing the therapeutic potential of immune and cell therapies while protecting patient safety in this rapidly expanding treatment landscape.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Cryogel Applications for Musculoskeletal Regeneration.","authors":"Dohee Kim, Shinwon Kang, Hyejin Jo, Inseon Kim, Seunghun S Lee","doi":"10.1002/med.70094","DOIUrl":"10.1002/med.70094","url":null,"abstract":"<p><p>Hydrogels have been widely used in tissue engineering due to their high-water content and biocompatibility, yet their densely cross-linked microstructure inherently limits cell infiltration, mass transport, and mechanical support. Cryogels, formed through partial freezing and crosslinking under subzero conditions, provide unique 3D macroporous networks with excellent permeability, elasticity, and shape-memory behavior. These structural and mechanical advantages facilitate cell migration and angiogenesis, while enabling minimally invasive delivery via syringe injection and highlighting strong translational potential. In musculoskeletal tissues such as bone, cartilage, and skeletal muscle, which have distinct biomechanical requirements, cryogels allow precise control over pore size, anisotropy, hierarchical architecture, and stiffness to better emulate native functionalities. Furthermore, tunable chemical composition and surface cues enable enhanced cell-matrix interactions and biological responsiveness. In addition, recent advances that incorporate growth factors, cells, nanomaterials, and conductive or immunomodulatory elements have established cryogels as therapeutic platforms that actively contribute to regeneration. These advancements further reinforce their clinical applicability and impact. This review summarizes the principles of cryogelation, crosslinking mechanisms, and structure-property relationships and examines recent cryogel-based strategies for musculoskeletal regeneration. By comparing fabrication parameters and their regenerative outcomes, we provide engineering insights for tissue-specific scaffold design and future optimization of cryogel-based musculoskeletal repair platforms.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senotherapeutics for Knee Osteoarthritis.","authors":"Ezgi Duman, Girish Pattappa, Patrick Pann, Stephan Reppenhagen, Maximilian Rudert, Peter Angele, Denitsa Docheva","doi":"10.1002/med.70082","DOIUrl":"https://doi.org/10.1002/med.70082","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a chronic disease that imposes a significant economic burden and deteriorates quality of life. Nevertheless, current therapeutic options for OA are limited to symptomatic remedies. As such, there is a high interest in novel methods for treating or preventing OA. One of the most promising medication modalities is through the clearance of cells that are cell cycle arrested but resistant to apoptosis, termed senescent cells. Additionally, these cells are also resistant to alternative programmed cell death modes, such as ferroptosis and pyroptosis. Senescent cells tend to accumulate with age due to increasing cellular and genetic damage. These cells can release inflammatory factors and signaling molecules termed senescence-associated secretory phenotype (SASP). In addition to triggering an inflammatory milieu in joints, SASP can also induce senescence in other cells through autocrine signaling. It has been shown via in vitro and in vivo tests that clearance of senescent cells through a class of drugs known as senolytics, or neutralization of SASP with senomorphics, can improve OA pathogenesis. Following these results, several clinical trials have been conducted to evaluate the efficacy of senotherapeutics against knee OA. Yet there remains a need for a comprehensive assessment of safety and optimization of senotherapeutic treatment regimens for knee OA. To this end, a better understanding of molecular mechanisms behind chondrocyte senescence and knee OA pathogenesis is necessary. Identification of novel compounds that can specifically target chondrocyte senescence pathways can assist in developing more effective therapies against OA.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Trends in Artificial Intelligence-Driven Drug Discovery: Balancing Chemical Design and Pharmacological Properties for Cancer Therapy.","authors":"Mohsin Ali, Muhammad Ali Tajwar, Farid Ahmed, Muhammad Muzammal Hussain, Wai-Yeung Wong, Hai Xiong","doi":"10.1002/med.70086","DOIUrl":"https://doi.org/10.1002/med.70086","url":null,"abstract":"<p><p>Traditional cancer drug discovery encounters challenges, including lengthy synthesis durations, high costs, and a 90% failure rate in clinical trials, primarily due to inadequate chemical design and drug properties. Artificial intelligence (AI) provides powerful computational tools to overcome these issues by speeding up target identification, predicting properties, and optimizing leads. This review emphasizes the influence of new AI platforms like AlphaFold3, molecular interactions are structurally optimized (MISATO), and ZairaChem on the discovery of oncology drugs. We specifically examine how AI reconciles chemical design with pharmacological feasibility. In addition to evaluating these advancements, we meticulously evaluate methodological challenges, including dataset bias, overfitting, insufficient external validation, and reproducibility issues. Furthermore, the development of complex and targeted modalities, such as antibody-drug conjugates (ADCs), aptamer-drug conjugates (Ap‑DCs), and proteolysis-targeting chimeras (PROTACs), is being explored for cancer treatment using AI. Following a detailed review of regulatory and clinical translation issues, this review presents practical tips for improving model validation, data sharing, and incorporation into medicinal chemistry workflows. By examining successes and persistent limitations, this review article offers a strategic roadmap for leveraging AI to provide clinically translatable cancer therapies with enhanced chemical and pharmacological balance.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsp90 Inhibition on the Western Blot: N-Terminal Versus C-Terminal Inhibitors in Breast Cancer.","authors":"Jaka Dernovšek, Jernej Cingl, Urša Pečar Fonović, Tihomir Tomašič","doi":"10.1002/med.70079","DOIUrl":"https://doi.org/10.1002/med.70079","url":null,"abstract":"<p><p>Heat shock protein 90 (Hsp90) is an established and clinically validated anticancer target. By regulating the folding and maturation of diverse client proteins, it is indirectly involved in carcinogenesis. Key breast cancer oncogenic drivers, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, are established Hsp90 clients, making breast cancer models widely used for Hsp90 inhibitor evaluation. However, N-terminal inhibitors are well known to induce a heat shock response (HSR), representing a major limitation in cancer therapy. This has driven the development of alternative modalities, such as C-terminal inhibitors, which in several cases avoid HSR induction. To evaluate Hsp90 inhibitors and characterize their proteomic effects, most studies employ western blotting (WB) as the primary method. On WB, different inhibitors are tested across various concentrations, time points, and breast cancer cell lines for their effects on client, heat shock, and other proteins. This generates extensive data sets that outline the expected WB performance of Hsp90 inhibitors. In this review, we focus on 10 protein families that are commonly used to assess Hsp90 inhibition in in vitro breast cancer models and represent all 10 cancer hallmarks. We provide basic structural and functional information on these families and comprehensively describe the effects of N- and C-terminal inhibitors on their levels. We summarize WB-based observations for more than 100 Hsp90 inhibitors, outlining the characteristic effects of N- and C-terminal inhibition, highlighting opportunities for future research, and ending with a suggestion for the WB method design based on best practices observed in literature.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The FGF/FGFR System in the Biology and Therapeutic Landscape of Pediatric CNS Tumors.","authors":"Serena Filiberti, Camilla Tavani, Elena Somenza, Nicolas Tassone, Antonio d'Amati, Marta Turati, Roberto Ronca","doi":"10.1002/med.70090","DOIUrl":"https://doi.org/10.1002/med.70090","url":null,"abstract":"<p><p>Central nervous system (CNS) tumors are the most common solid malignancies in children, comprising a highly heterogeneous group of neoplasms defined by distinct molecular alterations and clinical behaviors. Advances in molecular genetics have underscored the relevance of specific signaling pathways in driving pediatric tumorigenesis, among which the fibroblast growth factors (FGFs) and their receptors (FGFRs) have emerged as critical regulators of CNS development and tumor biology. The strict regulation of this system is frequently disrupted in cancer contexts, leading to abnormal activation that promotes tumor growth, invasion, and therapy resistance. Recent genomic profiling studies confirm that FGFR gene aberrations (i.e., activating point mutations, amplifications, and fusions) occur in a non-negligible fraction of pediatric CNS tumors. Notably, FGFR alterations are found in approximately 9% of pediatric gliomas, representing a higher incidence compared to adult gliomas. Across a broader survey of pediatric solid and brain tumors, activating FGFR aberrations were measurable in approximately 3% of cases. This prevalence establishes the FGF/FGFR axis as a measurable therapeutic vulnerability in defined patient subsets. Therefore, a deeper understanding of the role of the FGF/FGFR system across different pediatric CNS tumor subtypes is essential for elucidating disease mechanisms and identifying novel therapeutic opportunities. This review outlines the characteristics of major pediatric CNS tumors and discusses the role and potential therapeutic targeting of the FGF/FGFR system.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PAK4 in the Tumor Immune Microenvironment: Biological Functions, Regulatory Mechanisms, and Targeted Therapeutic Strategies.","authors":"Yiming Wang, Wuxiyar Otkur, Maosheng Cheng, Hanxun Wang, Mingyu Xia","doi":"10.1002/med.70083","DOIUrl":"https://doi.org/10.1002/med.70083","url":null,"abstract":"<p><p>p21-activated kinase 4 (PAK4), a critical effector of Ras homologous (Rho) GTP hydrolases (GTPases), promotes tumor progression and confers resistance to therapy by regulating malignant cellular phenotypes-such as proliferation, metastasis, and evasion of apoptosis-as well as by remodeling the tumor microenvironment (TME). Within tumor cells, PAK4 promotes proliferation by activating phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. It enhances invasive and metastatic potential through cytoskeletal reorganization mediated by phosphorylation of effector proteins such as LIM domain kinase 1 (LIMK1)/cofilin and actin nucleation-promoting factor WASL (N-WASP). Furthermore, PAK4 facilitates immune evasion by stabilizing programmed cell death ligand 1 (PD-L1) and inhibiting pyroptosis. At the TME level, PAK4 is activated by hypoxia-inducible factor 1-alpha (HIF-1α), inflammatory cytokines, and extracellular matrix (ECM) stiffness. This activation reprograms the immune landscape, induces aberrant angiogenesis, and promotes metabolic acidosis via the Warburg effect, collectively fostering an immunosuppressive and therapy-resistant niche. Small-molecule PAK4 inhibitors (e.g., KPT-9274, PF-3758309, compound 55) and degraders (e.g., CPS-021) effectively suppress tumor growth in preclinical models. Combining these agents with immune checkpoint blockade, chemotherapy, or radiotherapy reverses therapy resistance and reprograms the TME. Elevated PAK4 expression correlates significantly with poor patient prognosis and resistance to immunotherapy, positioning it as both a predictive biomarker and a promising therapeutic target. Elucidating the PAK4-TME axis provides a mechanistic foundation for developing novel combinatorial strategies targeting the tumor microenvironment.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-Driven Multi-Omics Integrated Applications Using Diverse Neural Networks for Breast Cancer Diagnostic Screening and Biomarker Discovery.","authors":"Vandana Kumari, Harshita Tiwari, Swati Singh, Vikas Kailashiya, Nguyen Thi Thu Hoai, Shikha Sachan, Brijesh Kumar, Rahul Kumar, Rajiv Kumar, Navin Kumar Verma, Vibhav Gautam","doi":"10.1002/med.70078","DOIUrl":"https://doi.org/10.1002/med.70078","url":null,"abstract":"<p><p>Breast cancer (BC) is a highly complex and heterogeneous malignancy and the most prevalent cancer among women worldwide. The diagnosis, prognosis, and the treatment of BC pose significant challenges that are responsible for their limited therapeutic efficacy. Omics-based technologies have gained substantial attention in BC diagnosis through molecular profiling and diverse clinical analytics. The integration of metabolomics, proteomics, transcriptomics, and genomics provides a multidimensional approach to personalized BC diagnosis and treatment through high-throughput molecular profiling. Moreover, the emergence of artificial intelligence (AI) has also supported more accurate and early diagnosis of BC through multimodal integration of diverse datasets. The integration of advanced deep learning (DL) and machine learning (ML) has been extensively exploited for tumor grading, histopathological classification, molecular profiling, diagnostic imaging, and prognostic prediction. This review aims to summarize recent developments in AI-driven multi-omics approaches for the discovery of BC biomarkers. We have also highlighted the integration of omics-based data like metabolomics, proteomics, transcriptomics, and genomics with key AI techniques, including ML and DL, that play a crucial role in the inclusion of multi-omics in cancer and biomarker discovery. We have further discussed AI-based BC screening and diagnostic approaches, as well as the contribution of AI models for patient stratification, biomarker discovery, and prediction of therapeutic response. Additionally, key limitations and challenges, including data heterogeneity, high computational complexity, and model interpretability, have also been highlighted in the present review. Conclusively, we have also outlined future perspectives on the integration of AI and multi-omics to revolutionize precision clinical medicine and improve clinical outcomes in BC theranostics.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drugging ERK1/2 in Cancer: A Glimpse of Small-Molecule Inhibitors.","authors":"Zhiqi Peng, Yuqi Fu, Yanmei Chen, Bo Fan, Bo Liu","doi":"10.1002/med.70084","DOIUrl":"https://doi.org/10.1002/med.70084","url":null,"abstract":"<p><p>The extracellular signal-regulated kinases 1 and 2 (ERK1/2) play central roles in the mitogen-activated protein kinase (MAPK) pathway and have emerged as critical regulators of tumorigenesis. Aberrant ERK1/2 signaling is frequently observed in cancers such as melanoma, pancreatic cancer, and colorectal cancer. This review outlines the historical milestones in ERK1/2 research, from their discovery and structural characterization to their identification as oncogenic drivers and therapeutic targets. We detail the ERK1/2 signaling network, highlighting key upstream regulators, including rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK), along with downstream substrates that mediate diverse oncogenic processes. Therapeutic approaches aimed at ERK1/2 currently fall into two main classes: small-molecule inhibitors with single-target specificity and those designed to simultaneously act on dual targets, along with combination therapies designed to overcome resistance and improve efficacy. Furthermore, we explore innovative approaches, including proteolysis-targeting chimeras (PROTACs), autophagy-targeting chimeras (AUTACs), and antibody-drug conjugates (ADCs), which offer promising avenues for selectively modulating ERK1/2 activity. By integrating mechanistic insights with clinical development trends, this review underscores the potential of ERK1/2-targeted therapies in precision oncology.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Small Molecule Research Targeting Monoacylglycerol Lipase in Drug Discovery.","authors":"Shuming Chen, Jun Yang, Weipeng Hu, Jing Gao, Li Chen, Jifa Zhang, Bowen Zhang, Wuyu Mao","doi":"10.1002/med.70089","DOIUrl":"https://doi.org/10.1002/med.70089","url":null,"abstract":"<p><p>Monoacylglycerol lipase (MAGL), a member of the endocannabinoid system (ECS), plays a crucial role in physiological processes such as regulating the signal transduction of the ECS and the eicosanoid system. In recent years, MAGL has been validated as a potential therapeutic target for several human diseases. Small-molecule MAGL inhibitors have shown considerable promise for the treatment of neurodegenerative diseases, depression, and cancer, with several candidates having advanced to clinical trials. This review briefly outlines the structural features and physiological functions of MAGL, highlights the associations between MAGL and human diseases, and systematically discusses small-molecule MAGL inhibitors developed for different disorders, with the goal of providing a reference for the discovery of more potent MAGL inhibitors.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}