ACS Pharmacology and Translational Science最新文献

{"title":"Tumor-derived Parathyroid Hormone-Related Protein Is Associated with Suppression of Cytochrome P450 Expression: Evidence From Multimodal Transcriptomics","authors":"Issei Fujita,&nbsp;Tsubasa Kaji,&nbsp;Isamu Noguchi,&nbsp;Kai Tokumaru,&nbsp;Hitoshi Maeda,&nbsp;Toru Maruyama,&nbsp;Hiroshi Watanabe","doi":"10.1021/acsptsci.6c00079","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00079","url":null,"abstract":"<p>Cancer cachexia is frequently associatedwith altered pharmacokineticsand increased chemotherapy toxicity due to the downregulation of cytochromeP450 (CYP) enzymes. However, the molecular mechanisms driving thisbroad metabolic suppression remain poorly understood. This study investigatedwhether tumor-derived parathyroid hormone-related protein (PTHrP)is associated with, and may contribute to, suppression of multipleCYP families. In a rat cachexia model, protein expression of CYP3A,CYP1A, CYP2C, CYP2D, and CYP2E1 was significantly downregulated inboth the liver and small intestine. Consistent with these changes,pharmacokinetic analyses using a CYP substrate cocktail demonstratedmarkedly increased AUC and reduced clearance for probe drugs. In vitroexperiments showed that PTHrP treatment reduced these CYP isoformsin primary rat hepatocytes. In human data sets, analysis of The CancerGenome Atlas (TCGA) hepatocellular carcinoma (HCC) data set revealeda significant negative correlation between PTHrP and CYP gene expression,together with enrichment of NF-κB-related transcriptional programs.Furthermore, multimodal analysis using single-cell RNA sequencingand spatial transcriptomics demonstrated that PTHrP-high tumor regionsexhibit suppressed xenobiotic metabolism. Additionally, in breastcancer liver metastases, high tumor PTHrP expression correlated withreduced CYP expression in surrounding nontumor hepatocytes, consistentwith a possible paracrine relationship. Collectively, these resultssupport an association between tumor-derived PTHrP and suppressionof drug-metabolizing programs. They further suggest that PTHrP maybe one contributing factor, but not definitive proof of a principalsuppressor, and should therefore be considered a candidate biomarkerrequiring further mechanistic and clinical validation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2234–2249"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Niacin−α-Lipoic Acid Hybrid Ameliorates Alzheimer’s Disease Pathology in Mouse Models","authors":"Weijia Peng,&nbsp;Cailv Wei,&nbsp;Jiasheng Liu,&nbsp;Jiakai Pi,&nbsp;Chenzhao Ding,&nbsp;Haiyan Guo,&nbsp;Xingxu Chen,&nbsp;Junfeng Lu,&nbsp;Runduo Liu,&nbsp;Wei Yin,&nbsp;Ge Zhang,&nbsp;Karl Wah-Keung Tsim,&nbsp;Rongbiao Pi","doi":"10.1021/acsptsci.6c00162","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00162","url":null,"abstract":"<p>Alzheimer’s disease (AD) is the most common neurodegenerativedisease with a rapid growth of patients worldwide in the aging era.Therefore, there is an urgent need to develop novel drugs for AD.Niacin and α-lipoic acid have been reported to exhibit therapeuticpotential in AD through distinct biological activities, includingGPR109A/HCAR2 agonism and antioxidant effects, respectively. N2L,a hybrid molecule derived from α-lipoic acid and niacin anda known GPR109A/HCAR2 agonist, has previously been reported to possesslipid-regulating, antiatherosclerotic, and ferroptosis-inhibitoryproperties. N2L is superior to niacin and/or lipoic acid alone dueto its longer half-life and the absence of flushing side effects.In this study, we evaluated the anti-AD efficacy of N2L in male mice,including both APP/PS1 transgenic familial AD mice and acrolein-inducedsporadic AD mice on the same C57BL/6 background. N2L significantlyattenuated amyloid-β deposition, tau hyperphosphorylation, glialactivation, synaptic degeneration, and ferroptosis in N2L-treatedAD mice brains. Additionally, N2L increased the relative abundanceof beneficial gut microbial taxa, including <em>Lactobacillus</em>, <em>Bifidobacterium</em>, and <em>Faecalibaculum</em>, suggesting a potential modulation of the microbiota–gut–brainaxis. These findings demonstrate that N2L exerts multifaceted protectiveeffects against AD-related pathological alterations and support itsfurther development as a potential therapeutic candidate for AD.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2250–2265"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Blockade of Hypoxia-Driven Autophagy: A Therapeutic Strategy to Limit Endothelial Activation and Thrombosis","authors":"Propanna Bandyopadhyay,&nbsp;Pragati Ramesh Kumbhar,&nbsp;Yash T. Katakia,&nbsp;Syamantak Majumder,&nbsp;Sudeshna Mukherjee,&nbsp;Gautam Singhvi,&nbsp;Rajdeep Chowdhury","doi":"10.1021/acsptsci.5c00770","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00770","url":null,"abstract":"<p>Thrombosis,a major underlying cause of cardiovascular disorders,is frequently initiated by endothelial cell (EC) activation, whichfacilitates platelet adhesion and subsequent clot formation. Althoughvascular injury is a well-established trigger, accumulating evidenceimplicates hypoxia as an additional determinant of thrombus development.In our previous study, we demonstrated that hypoxia associated withhigh altitude can promote autophagy-induced platelet aggregation.However, the contribution of ECs to such thrombosis under comparablehypoxic conditions (10%) remains poorly understood. In this study,using ECs isolated from rat aorta <em>ex vivo</em>, we showthat hypoxia-inducible factor-1 alpha (HIF-1α), a key transcriptionfactor, regulates autophagy and subsequent EC activation. Importantly,pharmacological inhibition of HIF-1α-mediated autophagy, repositioningthe FDA-approved drug chloroquine (CQ), led to attenuated expressionof P-Selectin, ICAM1, VCAM1 and consequent reduced platelet adhesionto ECs. Further mechanistic analysis revealed that autophagy modulatesthe NF-κB signaling pathway, in which P65 transcriptionallyregulates the adhesion molecules ICAM1 and VCAM1 by binding to theirupstream promoter elements under hypoxic conditions. In addition,using a rat IVC ligation model, we found that CQ not only attenuatesthrombus formation but also suppresses VCAM1 expression, validatingits antithrombotic potential. In summary, our findings suggest thathypoxia-induced HIF-1α activation promotes an autophagy-dependentNF-κB signaling cascade, thereby contributing to endothelialactivation and thrombus formation. Furthermore, CQ’s abilityto disrupt this pathway underscores the therapeutic potential of targetingendothelial autophagy to mitigate hypoxia-associated thrombosis.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2184–2197"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Role of Ferroptosis in Chemotherapy-Associated Hepatorenal Toxicity: Mechanistic Insights and Toxicological Perspectives","authors":"Vanktesh Kumar,&nbsp;Stalin Arulsamy,&nbsp;Wajid Aslam Khan,&nbsp;Shivank Sharma,&nbsp;Pinky Arora,&nbsp;Shubham Kumar","doi":"10.1021/acsptsci.6c00303","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00303","url":null,"abstract":"<p>Chemotherapy-induced hepatorenal toxicity is one of themost predominantdose-limiting obstacles in oncological pharmacotherapy, and the molecularmechanisms surrounding its pathogenesis are still poorly defined.Lipid peroxide toxicity-induced, iron-dependent, nonapoptotic typesof regulated cell death called ferroptosis have emerged as a mechanicallyimportant process in the organ injury caused by chemotherapy. In thisKeynote Review, we will summarize recent evidence showing the implicationof ferroptosis in liver and kidney toxicity of platinum-based drugs,anthracycline drugs, tyrosine kinase inhibitors, and some targeteddrugs. We identify key mechanisms underlying ferroptosis, includingabnormalities of the axis of system Xc^–/glutathioneperoxidase4 (GPX4) axis, changes in iron homeostasis, and activationof ferritinophagy and the maladaptive effects of polyunsaturated fattyacid oxidation. The role of the hepatorenal microenvironment is discussedin detail, with a particular focus on mitochondrion-related abnormalities,interaction between endocrine and immune cells, and mitochondrion-endoplasmicreticulum-stress coupling, as well as interactions with ferroptosissuppressor protein 1 (FSP1)/CoQ10 and dihydroorotate dehydrogenase(DHODH) pathways. Data from the preclinical models are combined withnew treatment data to develop a linear toxicological story. The utilityof the use of biomarker strategies such as plasma malondialdehyde,4-hydroxynonenal adducts, circulating GPX4, and urinary prostaglandin-likeisoprostanes in diagnosis and monitoring is examined. The role oftherapeutic interventions such as Nrf2 activators, liproxstatin1,ferrostatin1, and iron chelators for reducing organ-specific ferroptoticinjury without reducing effectiveness as antineoplastic is brieflyexplored. This Review highlights ferroptosis as a therapeutic targetthat is amenable to therapy and suggests a systematic approach forits integration into toxicological risk classifications during drugdevelopment for cancer treatment.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2117–2136"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of Long-Acting Intravitreal Hydrogels: A Comprehensive Evaluation of Intraocular Pressure and Retinal Integrity across Rabbit and Non-Human Primate Models","authors":"Alexa K. Beathard-Wojan,&nbsp;Becci Boughner,&nbsp;Vibhuti Agrahari","doi":"10.1021/acsptsci.6c00243","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00243","url":null,"abstract":"<p>Injectable hydrogels have emerged as promising platformsfor sustaineddrug delivery to the posterior segment of the eye, with the potentialto reduce treatment burden and improve patient adherence in chronicdisease management. Although numerous preclinical studies report favorablebiocompatibility and biodegradability, the effects of intravitreal(IVT) hydrogels on the ocular environment have yet to be comprehensivelyevaluated. In this study, we conducted a meta-analysis of preclinicalinvestigations evaluating IVT, drug-loaded hydrogels in rabbit andnonhuman primate models. Primary safety end points included longitudinalchanges in intraocular pressure (IOP) and total retinal thickness(TRT). Across all included studies, no significant or sustained elevationsin IOP were observed relative to baseline or untreated controls. TRTremained stable for 14 days up to two months postadministration, withno evidence of clinically meaningful thinning, degeneration, or retinaltoxicity. These outcomes were consistent across diverse hydrogel compositions,therapeutic payloads, gelation mechanisms, and animal models, indicatinga broadly favorable intraocular safety profile. Collectively, thisanalysis provides quantitative evidence supporting the ocular safetyof IVT hydrogel-based drug delivery systems based on IOP and TRT measurementsin preclinical models. These findings reinforce the translationalpotential of injectable hydrogels as biocompatible, long-acting alternativesto conventional IVT injection–based therapies and support theircontinued development for intraocular applications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2105–2116"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of Adebrelimab plus Apatinib Combined with Hepatic Artery Infusion Chemotherapy for the Treatment of Unresectable Hepatocellular Carcinoma: A Retrospective Study","authors":"Bin Chen,&nbsp;Yilin Zeng,&nbsp;Karima Abdugheni,&nbsp;Linyuan Zeng,&nbsp;Haitao Dai,&nbsp;Keyu Tang,&nbsp;Guiyuan Zhang,&nbsp;Jianyong Yang,&nbsp;Yonghui Huang,&nbsp;Run Lin","doi":"10.1021/acsptsci.6c00291","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00291","url":null,"abstract":"<p>The combined therapy of immune checkpoint inhibitors(ICIs) andtyrosine kinase inhibitors (TKIs) is now an approved first-line approachfor unresectable hepatocellular carcinoma (HCC). Hepatic arterialinfusion chemotherapy (HAIC) with the FOLFOX regimen (oxaliplatin,fluorouracil, and leucovorin) has also shown promising outcomes foradvanced HCC. However, the efficacy of these two therapeutic strategiesremains to be further improved. This retrospective study evaluatedthe safety and the efficacy of combining adebrelimab (a PD-L1 inhibitor),apatinib (a TKI), and FOLFOX-HAIC for unresectable HCC. The medicalrecords of unresectable HCC patients who received adebrelimab, apatinib,and FOLFOX-HAIC from March 2023 to November 2023 at the First AffiliatedHospital of Sun Yat-sen University (FAH-SYSU) were retrospectivelyreviewed. Safety was assessed by the frequency and severity of adverseevents (AEs), and efficacy was evaluated by tumor response criteriaincluding objective response rate (ORR), disease control rate (DCR),progression-free survival (PFS), and overall survival (OS). A totalof 19 patients were enrolled. There was no treatment-related death.The most frequent grade ≥ 3 treatment-related AEs were increasedALT/AST (47.4%) and thrombocytopenia (15.8%). The ORR was 26.3% and57.9% <em>as per</em> RECIST 1.1 and mRECIST, respectively.The DCR was 84.2% and 89.5% <em>as per</em> RECIST 1.1 andmRECIST, respectively. The median PFS was 9.0 months by both RECIST1.1 and mRECIST, and median OS was 22.0 months. The combination ofadebrelimab, apatinib, and FOLFOX-HAIC showed manageable safety andencouraging efficacy for unresectable HCC. This regimen may representa novel therapeutic option for advanced HCC and warrants further investigation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2282–2290"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fish Collagen Hydrolysates in Wound Healing: A Patent Review","authors":"Pamela Cunha Bortoluzzi,&nbsp;Rebeca Mello Chaves,&nbsp;Cecília de Azevedo Marques,&nbsp;Maíra Barroso Pereira,&nbsp;Lana Grasiela Alves Marques,&nbsp;Rodrigo Silveira Vieira,&nbsp;Fábia Karine Andrade","doi":"10.1021/acsptsci.6c00186","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00186","url":null,"abstract":"<p>The wound healingprocess typically consists of four stages; however,it can be delayed by several external factors, including bacterialcontamination, irritation from dressings, and internal conditionssuch as diabetes, etc. These challenges have driven a growing interestin advanced dressings incorporating bioactive materials, which canprotect the wound while simultaneously promoting healing. Collagenpeptides derived from collagen hydrolysis have gained increasing attentionin this context due to their bioactive properties. Notably, fish collagenhas gained prominence in recent years due to its favorable profilecompared to traditional sources. These attributes make fish collagenpeptides highly advantageous for use in wound care. In this context,literature and patent searches were conducted to assess the applicationof these materials in the context of biomaterial production and woundhealing. An initial screening resulted in 289 patents from the EuropeanPatent Office and Cortellis Drug Discovery Intelligence, of which10 were deemed eligible. The largest concentration of patents originatedin China (<em>n</em> = 6), Japan and Taiwan (<em>n</em> = 2 for both). These patents focused on topical cosmetics and oralformats, which are cosmetic products without a primary focus on therapeuticuse. The effects cited in the patents include cell and collagen proliferation,skin hydration, scar repair, antiaging, antioxidant activity, etc.Therefore, it was concluded that there has been an increase in theapplication of collagen peptides in recent years and that there areseveral benefits regarding the appearance and repair of the skin,making it interesting to conduct in-depth future research, includingclinical trials.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2092–2104"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Partition-Controlled Kinetic Model for Drug Release from Polymeric Nanocapsules: Resolving the Solubility Paradox","authors":"Maria Antonia S. de Albuquerque,&nbsp;Douglas F. de Albuquerque","doi":"10.1021/acsptsci.6c00265","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00265","url":null,"abstract":"<p>Mathematical descriptions of drug release from polymericnanocapsulesare commonly based on first-order kinetics derived from the Noyes–Whitneyequation. However, previous formulations implicitly predict that increasingdrug solubility in the oily core accelerates release, which contradictsexperimental evidence. In this work, we revisit the modeling frameworkand derive a physically consistent equation based on diffusion throughthe polymeric shell coupled with partition equilibrium at the oil–waterinterface. The resulting model shows that release kinetics are governedby the dimensionless partition–solubility group<span><span></span><math><msub><mi>Π</mi><mi>S</mi></msub><mo>=</mo><mfrac><msub><mi>S</mi><mn>0</mn></msub><mi>S</mi></mfrac></math></span> where <em>S</em>₀ denotesthe solubility of a reference formulation (<em>S</em>₀ = 1 mg mL^–1) and <em>S</em> isthe drug solubility (mg mL^–1). Accordingly, <em>k</em>_obs = <em>k</em>Π_<em>S</em>, so that the inverse-solubility effect emerges fromrelative partitioning behavior rather than from absolute solubilityalone. This formulation resolves the apparent paradox, preserves theexperimentally observed exponential saturation behavior, and collapseskinetic data into a single intrinsic parameter. We further demonstratethat the only prior model proposed specifically for nanocapsular systemsalso embeds the solubility paradox, and show that its own publishedvalidation data in fact confirm the inverse-solubility scaling derivedhere, with a deviation of only ∼9% between two independentformulations. Dimensional consistency, comparison with classical andnanoscale-specific models, and validation using published data supportthe robustness of the proposed approach.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2304–2311"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Candidate Small Molecule Targeting Tachykinin Receptor 1 Suppresses Substance P-Driven Extracellular Signal-Regulated Kinase Activation and Tumor Innervation in Pancreatic Cancer","authors":"Min Xiao,&nbsp;Huiya Cheng,&nbsp;Heteng Zhang,&nbsp;Zitong Zhang,&nbsp;Yuhan Sun,&nbsp;Zihui Ding,&nbsp;Heng Liang,&nbsp;Arabella Wan","doi":"10.1021/acsptsci.6c00306","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00306","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) is characterizedby extensivetumor-nerve interactions that contribute to tumor progression, therapeuticresistance, and neural remodeling. Substance P (SP) and its receptortachykinin receptor 1 (TACR1) have been implicated in cancer-associatedneurogenic signaling, but pharmacological strategies to interceptthis axis in PDAC remain insufficiently explored. Here, we identifiedTACR1 as a candidate druggable receptor expressed in pancreatic cancercells and used structure-guided virtual screening of a mini-scaffoldcompound library to prioritize small molecules with predicted TACR1-bindingpotential. Among the top-ranked compounds, C547 showed TACR1 targetengagement in cellular thermal shift assays and preferentially suppressedSP-induced growth and proliferation in TACR1-high MIA PaCa-2 cells,with limited effects in TACR1-low PANC-1 cells. C547 also attenuatedSP-induced migration, reversed SP-associated reduction in gemcitabinesensitivity, and reduced the expression of epithelial–mesenchymaltransition- and neurotrophin-associated genes. Mechanistically, SPincreased ERK phosphorylation, whereas C547 reduced SP-driven ERKactivation. Importantly, TACR1 knockdown diminished the inhibitoryeffects of C547 on cell growth and migration, supporting TACR1-dependentpharmacological activity. In an orthotopic KPPC pancreatic cancermodel, C547 reduced tumor burden and decreased PGP9.5-positive tumorinnervation without overt gross toxicity. These findings nominatethe SP–TACR1-ERK axis as a pharmacologically targetable neuro-oncogenicpathway in PDAC and support C547 as a candidate TACR1-targeting leadcompound for further optimization.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"2312–2323"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantum-Augmented Federated AI for Adaptive Pharmacogenomic Precision Oncology: A Perspective","authors":"Zahid Rafiq,&nbsp;Nahum Puebla Osorio","doi":"10.1021/acsptsci.6c00261","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00261","url":null,"abstract":"<p>Precision oncology has evolved from single-gene biomarkertestingtoward multimodal molecular and clinical profiling; however, mosttherapeutic decisions remain based on static baseline assessmentsthat inadequately capture tumor evolution, treatment response, andemerging resistance. In this perspective, we propose a forward-lookingframework that integrates federated learning, pharmacogenomic digitaltwins, and hybrid quantum–classical optimization to supportthe development of adaptive, privacy-preserving precision oncologysystems. The framework enables collaborative model training acrossinstitutions without sharing raw patient data, thereby addressingmajor barriers associated with data fragmentation and privacy regulations.Patient-specific digital twins serve as continuously evolving computationalrepresentations that integrate longitudinal multiomics, imaging, pathology,and clinical information to simulate disease trajectories, estimatetherapeutic response, and anticipate resistance patterns. Federatedlearning allows these models to benefit from geographically distributedpatient cohorts while maintaining data sovereignty and institutionalprivacy. In contrast to near-term deployable components such as federatedlearning and digital twin modeling, quantum computing is presentedas a future-oriented computational strategy that may assist selectedcombinatorial optimization tasks, including treatment selection, doseoptimization, and scheduling, through hybrid quantum–classicalworkflows. Rather than assuming immediate clinical utility or quantumadvantage, the framework emphasizes realistic translational pathwaysthat acknowledge current limitations in quantum hardware, scalability,validation, and regulatory readiness. We further discuss technicalfeasibility, challenges associated with heterogeneous clinical data,privacy considerations, validation requirements, and regulatory pathwaysfor adaptive AI-enabled clinical decision-support systems. By providinga formal conceptual architecture and translational roadmap, this perspectiveoutlines how federated artificial intelligence, continuously learningdigital twins, and future quantum-assisted optimization may collectivelycontribute to the next generation of adaptive precision oncology.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 8","pages":"1985–1993"},"PeriodicalIF":3.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}