Pharmacological Reviews最新文献

{"title":"miR-155 aberrant expression impairs tumor rejection because of its targeting of ICOSL and multiple pathways implicated in the antitumor response.","authors":"Esmerina Tili, Jean-Jacques Michaille, Carlo M Croce","doi":"10.1016/j.pharmr.2025.100088","DOIUrl":"10.1016/j.pharmr.2025.100088","url":null,"abstract":"<p><p>Cancer treatments have dramatically improved because of advances in surgery, radiotherapy, and chemotherapy. Although the duration of remission has steadily increased in recent years, preventing metastasis and achieving complete remission is still beyond reach for various types of cancers. However, recent advancements in immunology have facilitated the development of immunotherapies aimed at enhancing the specificity and efficacy of natural anticancer immune responses while impairing the inhibitory effects of immune checkpoints. Although immunotherapies combined with other treatment modalities have already produced remarkable results in previously untreatable tumors, many patients still do not achieve complete remission. In this review, we explore the effects of miR-155, a microRNA that plays a critical role in initiation and resolution of both innate and adaptive immunity. Among the many target transcripts of miR-155 are those encoding immune checkpoints, cell cycle regulators, epigenetics regulators, transcription factors, DNA repairs factors, and factors involved in various signaling pathways. The inhibitory effects of miR-155 on its target transcripts are likely to be context- and dose-dependent. As certain miR-155 targets can have opposing effects based on their dose and activity, therapies aimed at increasing or decreasing miR-155 levels can potentially backfire, inhibiting the beneficial effects of widely used anticancer drugs. Precise monitoring and adjustment of miR-155 levels, depending on the type and stage of tumors, should enhance the effectiveness of immunotherapies and increase the percentage of patients achieving complete remission in the future, particularly when immunotherapies are combined with chemotherapies. SIGNIFICANCE STATEMENT: Although immunotherapies developed the last decade have brought hope and improved cancer treatments, prevented metastasis, and increased the rate of complete remission, many aspects of the anticancer immune response are controlled by miR-155, a microRNA whose activity is both context- and dose-dependent. Therefore, it is essential to determine the optimal levels of miR-155 activity according to the type and stage of tumors, in order to fully unlock the potential of immunotherapies in combination with surgery, radiotherapies, or chemotherapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100088"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational drug design in the artificial intelligence era: A systematic review of molecular representations, generative architectures, and performance assessment.","authors":"Karim Abbasi, Parvin Razzaghi, Ali Gharizadeh, Amin Ghareyazi, Abbas Dehnad, Hamid R Rabiee, Mohammad R K Mofrad","doi":"10.1016/j.pharmr.2025.100095","DOIUrl":"10.1016/j.pharmr.2025.100095","url":null,"abstract":"<p><p>Generative drug design has emerged as a transformative approach in pharmaceutical research, leveraging deep learning models to create novel molecules with targeted properties. This systematic review analyzes the current landscape of computational approaches across 3 critical dimensions: molecular representation strategies (1-dimensional, 2-dimensional, and 3-dimensional), generative architectural frameworks (including variational autoencoders, generative adversarial networks, reinforcement learning systems, and diffusion models), and evaluation methodologies. We provide a comprehensive categorization of these approaches, critically assessing their relative advantages and limitations. Additionally, we examine the datasets driving development in this field and the metrics employed to evaluate model performance. Through structured analysis of these interconnected components, we identify significant research gaps and propose promising future directions for advancing artificial intelligence-driven drug discovery. This review offers researchers a unified framework for understanding the complex interplay between representation choices, generative mechanisms, and evaluation paradigms in computational drug design. SIGNIFICANCE STATEMENT: This review provides a unique framework for generative drug design by categorizing methods first by drug representation and then by generative model type. This novel taxonomy clarifies which models are best suited for specific molecular data types, offering practical guidance for researchers. We also critically discuss the advantages, disadvantages, key datasets, and evaluation metrics, delivering a comprehensive and actionable resource for the field.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100095"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752087","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":"Animal models of attention-deficit/hyperactivity disorder: Diversity and validity.","authors":"Bou Sader Nehme Sarah, Sánchez-Sarasúa Sandra, Medrano Mari-Carmen, Bouchatta Otmane, Bitar Tania, Alameddine Abbas, Galineau Laurent, Brunault Paul, Kerekes Nóra, Sanchez-Perez Ana-Maria, Hleihel Walid, Landry Marc","doi":"10.1016/j.pharmr.2025.100108","DOIUrl":"10.1016/j.pharmr.2025.100108","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is one of the most widespread neurodevelopmental disorders globally, marked by chronic symptoms of inattention and/or hyperactivity-impulsivity. Its multifactorial origin and phenotypic heterogeneity make it a complex condition, and despite substantial research, the precise causes of ADHD remain poorly understood. A significant challenge in advancing ADHD research is the lack of a unified resource that consolidates animal models across different species and considers the diversity of ADHD subtypes and associated coexisting conditions. This lack of standardization of the models delays progress in developing a deeper understanding of the neuronal and molecular mechanisms behind the disorder, which is essential to advance its treatment. This review aims to bridge this gap by offering a comprehensive compilation of available animal models used in ADHD research, accompanied by an evaluation of their validity. It is essential for researchers to have access to a range of models, each selected based on the specific scientific objectives and hypotheses of their studies. The review highlights that an extensive approach to studying ADHD, including its various dimensions and associated conditions, requires the use of multiple animal models. Moreover, it emphasizes the importance of assessing the mechanisms and broader effects of current pharmacological treatments while also exploring novel therapeutic possibilities. By providing a clearer and more structured resource, this work pursues to assist researchers in selecting the most appropriate models for their investigations. Additionally, it aims to contribute to the broader understanding of ADHD neurobiology, offering new perspectives for new models and the potential for more targeted therapeutic strategies. SIGNIFICANT STATEMENT: Attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent neurodevelopmental disorders globally, is marked by inattention and/or hyperactivity-impulsivity. This review evaluates animal models for ADHD and its coexisting conditions, emphasizing the need for diverse models to reflect its complexity. It underscores the importance of selecting appropriate models to address specific research goals and investigates current and potential pharmacological treatments, providing a vital resource for advancing ADHD research and improving therapeutic approaches.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100108"},"PeriodicalIF":20.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965923","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":"Targeting fatty acid synthase for cancer drug discovery: Retrospective analyses and outlook.","authors":"Qingbin Cui, Sophia Josephraj, Boqing Gu, Jing-Yuan Liu, Jian-Ting Zhang","doi":"10.1016/j.pharmr.2025.100105","DOIUrl":"10.1016/j.pharmr.2025.100105","url":null,"abstract":"<p><p>Enhanced de novo lipogenesis is a hallmark of cancer cells, enabling their proliferation, metastasis, and resistance to therapy. Among key lipogenic enzymes, fatty acid synthase (FASN) is frequently overexpressed in cancer but minimally expressed in most normal adult tissues, making it an appealing drug target. Human FASN is the sole cytosolic type I enzyme responsible for the de novo synthesis of palmitate. It is a homodimer of 270 kDa multidomain protein, functioning like an automatic assembly line. Its acyl carrier protein domain serves as a flexible arm, transporting the elongating acyl chain through other enzymatic domains responsible for chain elongation and modification, including malonyl/acetyltransferase, β-ketoacyl synthase, enoyl reductase, β-ketoacyl reductase, dehydrase, and thioesterase. The process begins at the malonyl/acetyltransferase domain, where the acetyl and malonyl groups from acetyl-CoA and malonyl-CoA, respectively, are transferred to the acyl carrier protein. FASN has been validated to play vital roles in promoting cancer progression, supporting cancer cell survival, reprogramming lipid metabolism, modulating oncogenic signaling pathways, and inducing drug resistance. Over the past 2 decades, significant progress has been made in developing inhibitors targeting different domains of FASN, including structure-based drug design, repurposing existing drugs, and nature-derived compounds with FASN-inhibitory properties. Despite these efforts, only a handful of inhibitors have entered clinical trials, such as 3-V Biosciences-2640 (denifanstat) and repurposed omeprazole, and none have received regulatory approval to date. In this review, we critically evaluate FASN-targeting strategies, highlight domain-specific targeting challenges, and discuss emerging insights that may help overcome current limitations, aiming to guide future discovery and optimization of FASN-targeted therapeutics. SIGNIFICANCE STATEMENT: Enhanced lipogenesis and fatty acid synthase overexpression in cancer make this multidomain enzyme an attractive target for therapy and overcoming drug resistance. Despite progress with novel and repurposed inhibitors, none have gained approval. This review critically examines past efforts, current challenges, and offers insights to guide future development of effective fatty acid synthase-targeting cancer therapeutics.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100105"},"PeriodicalIF":20.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13169002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence-assisted drug discovery in 2025: Faster, but is it better? The robots are coming, look out!","authors":"Mahendiran Dharmasivam,Mahan Gholam Azad,Vera Richardson,Busra Kaya,Des R Richardson","doi":"10.1016/j.pharmr.2025.100103","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100103","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"1 1","pages":"100103"},"PeriodicalIF":21.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664306","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":"Resolution Pharmacology: State-of-the-art and therapeutic landscape.","authors":"Mauro Perretti, Trinidad Montero-Melendez","doi":"10.1016/j.pharmr.2025.100097","DOIUrl":"10.1016/j.pharmr.2025.100097","url":null,"abstract":"<p><p>In 2015, we coined the term \"Resolution Pharmacology\" to indicate how the biology of the resolution of inflammation could, and should, be harnessed to produce novel therapeutics. Here we update these concepts and discuss the most recent developments in this innovative field of pharmacology. We begin by discussing how the inflammatory response is lifesaving through the engagement, expression, and function of several mediators, which have been labeled as proinflammatory or proresolving mediators. In reality, they act in concert and regulate each other in a fully integrated fashion, so that the notion between inflammation onset and inflammation resolution, as 2 distinct phases, is mainly didactic and temporal. Moreover, the observation that the inflammatory reaction that our body mounts always, or nearly always, resolves indicate that inflammation resolution is a robust process. What remain to be addressed, though, is how to harness the biology of acute resolving inflammation so that innovative therapeutic options can be offered for the clinical management of chronic nonresolving inflammation. The holistic view of physiological inflammation, and its disruption in pathology, comes with implications in relation to the application of Resolution Pharmacology. We predict resolution-based drugs will work better in presence of a florid inflammatory status, which would augment expression of resolution targets. We conclude by proposing a renovated focus on endogenous tissue-protective regenerative pathways by specific targets for drug development programs: Resolution Pharmacology remains an untapped opportunity for the pharmaceutical industry. SIGNIFICANCE STATEMENT: The process of the resolution of inflammation represents an integral part of the whole acute inflammatory response. A florid inflammatory reaction ensures proper engagement of resolution mechanisms. Dysregulation in resolution mechanisms can lead to disease. Conversely, harnessing resolution can offer therapeutic guidance to develop medicines that are disease independent, broadening their potential. There is ongoing intensive clinical development in this area. Proresolving drugs will be patient centric in their pharmacology and would promote natural processes of healing and repair.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100097"},"PeriodicalIF":20.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological functions and pharmacological targeting of transient receptor potential channels.","authors":"Vladimir Chubanov, Christian Grimm, Kerstin Hill, Michael Schaefer, Michael Köttgen, Ursula Storch, Michael Mederos Y Schnitzler, Veronika Kudrina, Anna Erbacher, Thomas Gudermann","doi":"10.1016/j.pharmr.2025.100089","DOIUrl":"10.1016/j.pharmr.2025.100089","url":null,"abstract":"<p><p>Transient receptor potential (TRP) channels represent an extensive and diverse protein family fulfilling salient roles as versatile cellular sensors and effectors. The pivotal role of TRP and related ion channels in sensory processes has been well documented. Over the last few years, a new concept has emerged that TRP proteins control an exceptionally broad spectrum of homeostatic physiological functions such as maintenance of body temperature, blood pressure, transmitter release from neurons, mineral and energy homeostasis, and reproduction. This notion is further supported by more than 20 hereditary human diseases in areas as diverse as neurology, cardiology, hematology, pulmonology, nephrology, dermatology, and urology. Most TRP channel-related human disorders impinge on development, metabolism, and other homeostatic functions. The remarkable diversity of pathologies caused by TRP channel dysfunction underscores these proteins' broad spectrum of roles in vivo. Here, we provide a comprehensive overview of our progress in the identification, characterization, and clinical relevance of pharmacological agents targeting mammalian TRP channels. SIGNIFICANCE STATEMENT: Accumulating evidence links transient receptor potential (TRP) channels to various human diseases and highlights TRPs as the most appealing pharmacological targets. The review provides an overview of this quickly developing research area, focusing on identified pharmacological modulators of mammalian TRP channels.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100089"},"PeriodicalIF":20.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the adenosinergic axis in cancer immunotherapy: Insights into A_2A and A_2B receptors and novel clinical combination strategies.","authors":"Iván Rodríguez-Pampín, Lucía González-Pico, Asier Selas, Antonio Andújar, Rubén Prieto-Díaz, Eddy Sotelo","doi":"10.1016/j.pharmr.2025.100092","DOIUrl":"10.1016/j.pharmr.2025.100092","url":null,"abstract":"<p><p>The extracellular accumulation of adenosine is a central mechanism of immune evasion within the tumor microenvironment. Elevated adenosine levels-driven by hypoxia, chronic inflammation, and upregulated ectonucleotidase activity, primarily through ectonucleoside triphophate diphosphoydrolase 1 and ecto-5'-nucleotidase-induce profound immunosuppression and promote tumor progression. In this setting, adenosine acts mainly through 2 G protein-coupled receptors, the adenosine A_2A receptor (A_2AAR) and the adenosine A_2B receptor (A_2BAR), which modulate diverse immune and stromal cell populations. A_2AAR signaling suppresses the effector activity of cytotoxic T lymphocytes and natural killer cells, whereas A_2BAR activation exerts broader effects by amplifying myeloid-derived immunosuppression, driving stromal remodeling, and fostering angiogenesis and metastatic dissemination. This review provides a comprehensive overview of the distinct and converging roles of A_2AAR and A_2BAR in immune, stromal, and tumor compartments. We critically analyze current strategies for developing selective and dual A_2AAR/A_2BAR antagonists, with a focus on structure-activity relationships, scaffold optimization, and pharmacokinetic profiling. In addition, we examine ongoing clinical trials and emerging combination therapies involving A_2AAR and A_2BAR antagonists in conjunction with immune checkpoint inhibitors, adoptive cell therapies, enzymatic axis blockade, radiotherapy, and classical chemotherapy. We also underscore the therapeutic potential of dual A_2AAR/A_2BAR antagonists as a multitarget approach to counteract overlapping immunosuppressive mechanisms. Overall, targeting the adenosine axis-particularly through dual receptor blockade-represents a promising strategy for reprograming the tumor microenvironment, reinvigorating antitumor immunity, and improving the efficacy of cancer immunotherapy. SIGNIFICANCE STATEMENT: Adenosine signaling via adenosine A_2A (A_2AAR) and A_2B (A_2BAR) receptors plays a central role in tumor-induced immunosuppression, limiting the efficacy of cancer immunotherapy. This review provides an integrated analysis of A_2AAR and A_2BAR functions across immune and stromal compartments, summarizes current selective antagonists (A_2AAR and A_2BAR) and dual antagonists, and highlights compounds in clinical studies. Moreover, it discusses synergistic combination strategies that integrate adenosine blockade with complementary immunotherapeutic and conventional approaches to enhance antitumor responses.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100092"},"PeriodicalIF":17.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308881","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 evolution of lipid-lowering drugs in the management of cardiovascular disease risk: From the first cardiovascular disease risk-reducing therapies to the novel challenging strategies.","authors":"Doriane Henry, Eric Baugé, Bart Staels, Fanny Lalloyer","doi":"10.1016/j.pharmr.2025.100086","DOIUrl":"10.1016/j.pharmr.2025.100086","url":null,"abstract":"<p><p>Before the Framingham Heart Study, the concept of cardiovascular disease (CVD) risk factors did not exist, and CVDs were seen as a consequence of aging. The first 2 reports in 1957 and 1961 identified high cholesterol levels as a major risk factor for CVD, highlighting the importance of lipid management to reduce CVD risk. Since then, the growing knowledge of CVD pathophysiology has led to the development of many drug classes to manage dyslipidemia and consequently, cardiovascular disease risk. Unfortunately, many of them, such as high-density lipoprotein-targeted or triglyceride-modulating drugs, have so far failed in clinical trials due to a lack of efficacy in cardiovascular disease protection or due to the appearance of side effects. Interestingly, low-density lipoprotein-targeted statin therapy revolutionized cardiovascular risk management and remains today the reference treatment in primary and secondary CVD prevention. In the last decades, novel low-density lipoprotein-targeted drugs, such as ezetimibe, proprotein convertase subtilisin/kexin type 9-targeted therapies, and bempedoic acid, have been approved by the Food and Drug Administration and have now found their place among the therapeutic arsenal of hypolipidemic drugs used in CVD risk management, in case of intolerance to statins or often in association with statins. This review focuses on the historical evolution of development strategies and on the successes and failures of lipid-lowering drugs to reduce cardiovascular disease risk, from the mid-20th century to the present, and concludes with novel challenging strategies in progress. SIGNIFICANCE STATEMENT: This review highlights the evolution of lipid-lowering therapies in atherosclerotic cardiovascular disease management, from statins to proprotein convertase subtilisin/kexin type 9 inhibitors. It underscores key successes, limitations, and emerging strategies, offering essential insights into their current and future roles in reducing atherosclerotic cardiovascular disease risk for a broad medical and scientific audience.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100086"},"PeriodicalIF":17.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058563","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":"Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.","authors":"Michael Karin, Ju Youn Kim","doi":"10.1016/j.pharmr.2025.100096","DOIUrl":"10.1016/j.pharmr.2025.100096","url":null,"abstract":"<p><p>The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100096"},"PeriodicalIF":20.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}