Pharmacological Reviews最新文献

{"title":"Pathological and therapeutic roles of bile acid metabolism and signaling in hepatocellular carcinoma: Insights from human and mouse studies.","authors":"Xue Wang, Curtis D Klaassen, Xin Chen, Youcai Zhang","doi":"10.1016/j.pharmr.2025.100073","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100073","url":null,"abstract":"<p><p>Bile acids (BAs), the end products of cholesterol catabolism, play a crucial role in various physiological and pathological processes. Defects in BA synthetic enzymes and transporters cause rare monogenic diseases. Dysregulation of BA homeostasis contributes to the pathogenesis and progression of various liver diseases, including hepatocellular carcinoma (HCC), the most common form of liver cancer. BA profiles are altered in patients with HCC and in mouse models of HCC, and their diagnostic potential is currently under clinical investigation. Growing evidence suggests that BA metabolism and signaling regulate key processes involved in HCC development. Recent advances in understanding the complex interactions between the gut microbiota and BAs have provided new insights into HCC. In this review, we summarize the current literature on BA quantification, detoxification, synthesis, transport, signaling functions, and the interplay between BAs and bacteria in the pathogenesis and progression of HCC, particularly in patients with HCC and mouse models. Furthermore, we discuss potential therapeutic strategies targeting BA metabolism and signaling as promising approaches for HCC treatment. SIGNIFICANCE STATEMENT: Bile acids hold promise as potential biomarkers for the diagnosis and prognosis of hepatocellular carcinoma. Modulating bile acid metabolism and signaling pathways represents a promising novel strategy for hepatocellular carcinoma treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100073"},"PeriodicalIF":19.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554132","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 the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.","authors":"Alina Brüge, Evgeni Ponimaskin, Josephine Labus","doi":"10.1016/j.pharmr.2025.100071","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100071","url":null,"abstract":"<p><p>More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100071"},"PeriodicalIF":19.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626813","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":"Cryoelectron microscopy as a tool for illuminating activation mechanisms of human class A orphan G protein-coupled receptors.","authors":"Isabella C Russell, Dongju Lee, Denise Wootten, Patrick M Sexton, Fabian Bumbak","doi":"10.1016/j.pharmr.2025.100056","DOIUrl":"10.1016/j.pharmr.2025.100056","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are critically important medicinal targets, and the cryogenic electron microscopy (cryo-EM) revolution is providing novel high-resolution GPCR structures at a rapid pace. Orphan G protein-coupled receptors (oGPCRs) are a group of approximately 100 nonolfactory GPCRs for which endogenous ligands are unknown or not validated. The absence of modulating ligands adds difficulties to understanding the physiologic significance of oGPCRs and in the determination of high-resolution structures of isolated receptors that could facilitate drug discovery. Despite the challenges, cryo-EM structures of oGPCR-G protein complexes are emerging. This is being facilitated by numerous developments to stabilize GPCR-G protein complexes such as the use of dominant-negative G proteins, mini-G proteins, complex-stabilizing nanobodies or antibody fragments, and protein tethering methods. Moreover, many oGPCRs are constitutively active, which can facilitate complex formation in the absence of a known activating ligand. Consequently, in addition to providing templates for drug discovery, active oGPCR structures shed light on constitutive GPCR activation mechanisms. These comprise self-activation, whereby mobile extracellular portions of the receptor act as tethered agonists by occupying a canonical orthosteric-binding site in the transmembrane core, constitutive activity due to alterations to conserved molecular switches that stabilize inactive states of GPCRs, as well as receptors activated by cryptic ligands that are copurified with the receptor. Cryo-EM structures of oGPCRs are now being determined at a rapid pace and are expected to be invaluable tools for oGPCR drug discovery. SIGNIFICANCE STATEMENT: Orphan G protein-coupled receptors (GPCRs) provide large untapped potential for development of new medicines. Many of these receptors display constitutive activity, enabling structure determination and insights into observed GPCR constitutive activity including (1) self-activation by mobile receptor extracellular portions that function as tethered agonists, (2) modification of conserved motifs canonically involved in receptor quiescence and/or activation, and (3) activation by cryptic lipid ligands. Collectively, these studies advance fundamental understanding of GPCR function and provide opportunities for novel drug discovery.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100056"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036362","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 microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player.","authors":"Yasmin Amy Divecha, Sanketh Rampes, Sabine Tromp, Sevda T Boyanova, Alice Fleckney, Mehmet Fidanboylu, Sarah Ann Thomas","doi":"10.1016/j.pharmr.2025.100052","DOIUrl":"10.1016/j.pharmr.2025.100052","url":null,"abstract":"<p><p>High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100052"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064345","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":"Application of Kirchhoff's Laws to pharmacologic and pharmacokinetic analyses.","authors":"Leslie Z Benet, Jasleen K Sodhi, Markus Ville Tiitto, Yue Xiang","doi":"10.1016/j.pharmr.2025.100050","DOIUrl":"10.1016/j.pharmr.2025.100050","url":null,"abstract":"<p><p>Recently, we introduced a straightforward approach to derive clearance and rate constant equations, without relying on differential equations, utilizing Kirchhoff's Laws, a well known physics methodology used to describe rate-defining processes either in series or parallel. Manuscripts from our laboratory have re-examined published experimental data, demonstrating that the Kirchhoff's Laws methodology can explain data previously considered anomalous, such as the following: (1) all experimental perfused liver clearance data conforming to the equation once thought to represent the unphysiological well stirred model, (2) instances where linear pharmacokinetic systemic bioavailability determinations exceed unity, (3) renal clearance being influenced by drug input processes, (4) statistically significant differences in bioavailability measures between urinary excretion and systemic concentration measurements, and (5) how the long-accepted steady-state clearance approach used in pharmacokinetics for the past half-century leads to unrealistic conclusions about the relationship between liver-to-blood Kp_uu and hepatic availability F_H. These findings demonstrate the potential for errors in pharmacokinetic evaluations that rely on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, both those that align with present pharmacokinetic theory, and those that do not. Although 3 publications have attempted to rebut our position, they fail to address unexplained experimental data, and we detail here why these analyses are invalid. Our discoveries are ongoing. Additionally, we briefly discuss the application of Kirchoff's Laws to saturable nonlinear kinetics, explaining increased pharmacodynamic response for extended vs immediate release dosage forms, as well as the advantages of successfully formulating high hepatic extraction drugs. SIGNIFICANCE STATEMENT: The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes anomalous published pharmacokinetic data that have previously been unexplained. We review 9 experimental outcomes in humans that are newly explained using the Kirchhoff's Laws approach, including the extension to deriving nonlinear saturable clearance relationships.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100050"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693087","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":"Cyclic nucleotide phosphodiesterases as drug targets.","authors":"Michy P Kelly, Viacheslav O Nikolaev, Leila Gobejishvili, Claire Lugnier, Christian Hesslinger, Peter Nickolaus, David A Kass, Walma Pereira de Vasconcelos, Rodolphe Fischmeister, Stefan Brocke, Paul M Epstein, Gary A Piazza, Adam B Keeton, Gang Zhou, Mohammad Abdel-Halim, Ashraf H Abadi, George S Baillie, Mark A Giembycz, Graeme Bolger, Gretchen Snyder, Kjetil Tasken, Nathaniel E B Saidu, Martina Schmidt, Manuela Zaccolo, Ralph T Schermuly, Hengming Ke, Rick H Cote, Soroush Mohammadi Jouabadi, Anton J M Roks","doi":"10.1016/j.pharmr.2025.100042","DOIUrl":"10.1016/j.pharmr.2025.100042","url":null,"abstract":"<p><p>Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100042"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625901","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":"Safety in treatment: Classical pharmacotherapeutics and new avenues for addressing maternal depression and anxiety during pregnancy.","authors":"Merel Dagher, Catherine M Cahill, Anne M Andrews","doi":"10.1016/j.pharmr.2025.100046","DOIUrl":"10.1016/j.pharmr.2025.100046","url":null,"abstract":"<p><p>We aimed to review clinical research on the safety profiles of antidepressant drugs and associations with maternal depression and neonatal outcomes. We focused on neuroendocrine changes during pregnancy and their effects on antidepressant pharmacokinetics. Pregnancy-induced alterations in drug disposition and metabolism impacting mothers and their fetuses are discussed. We considered evidence for the risks of antidepressant use during pregnancy. Teratogenicity associated with ongoing treatment, new prescriptions during pregnancy, or pausing medication while pregnant was examined. The Food and Drug Administration advises caution regarding prenatal exposure to most drugs, including antidepressants, largely owing to a dearth of safety studies caused by the common exclusion of pregnant individuals in clinical trials. We contrasted findings on antidepressant use with the lack of treatment where detrimental effects to mothers and children are well researched. Overall, drug classes such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors appear to have limited adverse effects on fetal health and child development. In the face of an increasing prevalence of major mood and anxiety disorders, we assert that individuals should be counseled before and during pregnancy about the risks and benefits of antidepressant treatment given that withholding treatment has possible negative outcomes. Moreover, newer therapeutics, such as ketamine and κ-opioid receptor antagonists, warrant further investigation for use during pregnancy. SIGNIFICANCE STATEMENT: The safety of antidepressant use during pregnancy remains controversial owing to an incomplete understanding of how drug exposure affects fetal development, brain maturation, and behavior in offspring. This leaves pregnant people especially vulnerable, as pregnancy can be a highly stressful experience for many individuals, with stress being the biggest known risk factor for developing a mood or anxiety disorder. This review focuses on perinatal pharmacotherapy for treating mood and anxiety disorders, highlighting the current knowledge and gaps in our understanding of consequences of treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100046"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582357","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":"Analyzing lognormal data: A nonmathematical practical guide.","authors":"Harvey J Motulsky, Trajen Head, Paul B S Clarke","doi":"10.1016/j.pharmr.2025.100049","DOIUrl":"10.1016/j.pharmr.2025.100049","url":null,"abstract":"<p><p>Lognormal distributions are pervasive in pharmacology and elsewhere in biomedical science, arising naturally when biological effects multiply rather than add. Despite their ubiquity in pharmacological parameters (eg, EC50, IC50, Kd, and Km), lognormal distributions are often overlooked or misunderstood, leading to flawed data analysis. This largely nonmathematical review explains why lognormal distributions are common, how to recognize them, and how to analyze them appropriately. We show that many measured variables are lognormal. So are many derived parameters, particularly those defined as ratios of lognormal variables. Through examples and simulations accessible to working scientists, we demonstrate how misidentifying lognormal distributions as normal leads to reduced statistical power, unnecessarily large sample sizes, false identification of outliers, and inappropriate reporting of effects as differences rather than ratios. We challenge the common practice of using normality tests to decide how to analyze data, showing that many data sets pass both normality and lognormality tests, especially with small sample sizes. Instead, we advocate for assuming lognormality based on the nature of the variable. This review provides practical guidance on recognizing and presenting lognormal data, and comparing data sets sampled from lognormal distributions. Based on Monte Carlo simulations, we recommend the lognormal Welch's t test or nonparametric Brunner-Munzel test for comparing 2 unpaired groups, the lognormal ratio paired t test for paired comparisons, and lognormal ANOVA for ≥3 groups. By recognizing and properly handling lognormal distributions, pharmacologists can design more efficient experiments, obtain more reliable statistical inferences, and communicate their results more effectively. SIGNIFICANCE STATEMENT: Lognormal distributions are common in pharmacology and many scientific fields, but they are often misunderstood or overlooked. This review provides a detailed guide to recognizing and analyzing lognormal data, aiming to help pharmacologists perform more appropriate and more powerful statistical analyses, draw more meaningful conclusions from their data, and communicate their results more effectively.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100049"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743522","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":"Corrigendum to \"Toward a paradigm shift: Oral agents and injectable drugs in the future of obesity management\" [Pharmacological Reviews 77 (2025) 100008].","authors":"Amirhossein Sahebkar, Ali H Eid","doi":"10.1016/j.pharmr.2025.100047","DOIUrl":"10.1016/j.pharmr.2025.100047","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100047"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582355","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":"Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.","authors":"Yuqi Fu, Jin Zhang, Rui Qin, Yueting Ren, Tingting Zhou, Bo Han, Bo Liu","doi":"10.1016/j.pharmr.2025.100053","DOIUrl":"10.1016/j.pharmr.2025.100053","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of \"chasing and escaping\" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100053"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788590","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}