Pharmacological research最新文献

{"title":"The TET/5hmC mediated epigenetic landscape in glioma: From molecular mechanisms to therapeutic targeting and future perspectives","authors":"Jiarong He ,&nbsp;Fei Peng ,&nbsp;Ying Xu ,&nbsp;Zhongyue Liu ,&nbsp;Kai Su ,&nbsp;Yang Zhou ,&nbsp;Yugang Jiang ,&nbsp;Ming Wang","doi":"10.1016/j.phrs.2026.108095","DOIUrl":"10.1016/j.phrs.2026.108095","url":null,"abstract":"<div><div>The DNA hydroxymethylation landscape is profoundly disrupted in gliomas, especially glioblastoma, marked by global loss of 5-hydroxymethylcytosine (5hmC) and impaired Ten-eleven translocation (TET) enzyme activity. This review synthesizes evidence that TET family expression and subcellular localization are systematically altered in glioma: TET1 undergoes nuclear exclusion, while TET2 and TET3 show reduced nuclear abundance, directly contributing to 5hmC depletion. The extent of 5hmC loss correlates with tumor grade yet exhibits subtype heterogeneity, including a unique “5hmC-high” glioblastoma subgroup, highlighting the importance of post-transcriptional control of TET protein levels. Upstream regulatory mechanisms involve transcription factors (e.g., SOX2-mediated repression and context-dependent STAT3 activation), non-coding RNAs (such as miR-10b), and epigenetic silencing of TET genes themselves, alongside metabolic and microenvironmental constraints (e.g., D-2-HG from IDH1/2 mutations, hypoxia) that restrict TET catalytic function. Downstream consequences include TET deficiency-driven promoter hypermethylation and MBD-mediated repression of tumor suppressor and differentiation genes, RNA hydroxymethylation-dependent regulation of mRNA stability and splicing, and chromatin reprogramming via interactions with complexes like OGT/COMPASS and PRC2. Functionally, TET inactivation promotes tumor initiation and progression, sustains glioma stem cells, enhances cellular plasticity, drives metabolic reprogramming, and facilitates immune evasion. Emerging therapeutic strategies encompass miRNA antagonists, vitamin C as a TET cofactor, DNMT and HDAC inhibitors, locus-specific epigenetic editing tools (e.g., CRISPR-dCas9 and engineered demethylases), brain-penetrant IDH inhibitors, and novel approaches such as PROTACs and TET mRNA delivery—all requiring precision application due to the context-dependent roles of TET proteins. We further identify critical research gaps, including single-cell and spatial mapping of TET/5hmC dynamics, microenvironmental regulation of TET activity, functional cooperation between TET isoforms, and the development of clinically feasible delivery systems and biomarkers. Addressing these challenges will be essential to translate TET pathway modulation into effective, individualized combination therapies for glioma patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108095"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Live cell luminescence-based Gα_q-PLC-β interaction assay: Development and application at the serotonin 5-HT_2A receptor.","authors":"Eline Pottie, Christophe P Stove","doi":"10.1016/j.phrs.2026.108094","DOIUrl":"10.1016/j.phrs.2026.108094","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) remain among the most important drug targets. To characterize their ligands' activity, a range of in vitro assays is available, all with their inherent advantages and limitations. In the Gα_q signaling pathway, the interaction between Gα_q and phospholipase C (PLC-)β is a receptor-proximal event, and its monitoring does not require modification of the GPCR. With this in mind, we set out to develop a luminescence-based assay gauging this interaction. The resulting assay format encompassed functional complementation of a split nanoluciferase following the interaction of SmBiT, N-terminally fused to PLC-β, with LgBiT, intramolecularly integrated within Gα_q. When applied to assess activation of the Gα_q-coupled serotonin 2 A receptor (5-HT_2AR), an excellent assay performance was demonstrated, as evidenced by an auspicious Z'-factor of 0.75 and by confirming the specificity for both the GPCR and the Gα_q signaling pathway. The optimized Gα_q-PLC-β assay was successfully applied on a diverse panel of 5-HT_2AR ligands and the resulting output was compared with that of a more upstream miniGα_q recruitment assay, and more downstream IP₁ accumulation and Ca²⁺ mobilization assays. Overall, the Gα_q-PLC-β assay yielded efficacy, potency and relative activity data that correlated very well with those obtained with the IP₁ accumulation and miniGα_q recruitment assays, although with the former two assays consistently higher potencies and a smaller range of efficacies were observed. Comparison with the Ca²⁺ mobilization assay did not yield such good correlation, presumably because of kinetic implications. Last, the Gα_q-PLC-β interaction assay allowed to detect signals emerging from endogenously expressed GPCRs, indicative of its broad applicability.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108094"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The addicted brain: How processed foods hijack reward pathways","authors":"Kaylee Hough ,&nbsp;Marzia Friuli ,&nbsp;Nicole M. Avena ,&nbsp;Adele Romano","doi":"10.1016/j.phrs.2026.108097","DOIUrl":"10.1016/j.phrs.2026.108097","url":null,"abstract":"<div><div>The concept of addiction, traditionally confined to substances such as drugs and alcohol, has expanded to encompass behavioral patterns such as compulsive eating. Emerging evidence suggests that ultra-processed foods (UPFs), particularly those high in refined sugars and saturated fats, may elicit neurobiological responses akin to those observed in substance use disorders. This review explores the hypothesis that food addiction shares common clinical and neurochemical mechanisms with traditional forms of addiction, drawing from DSM-5 diagnostic criteria and recent findings in neuropharmacology. Animal and human studies have demonstrated that excessive consumption of palatable foods can induce behaviors characteristic of addiction—bingeing, craving, tolerance, and withdrawal—accompanied by significant dopaminergic alterations within the mesolimbic reward circuitry. Neuroimaging and molecular studies further reveal that chronic overconsumption of UPFs alters dopaminergic tone, disrupts prefrontal control, and activates stress pathways, thereby reinforcing compulsive intake. The Yale Food Addiction Scale (YFAS) and its pediatric adaptations provide structured tools for identifying food addiction phenotypes in clinical and research settings. Moreover, parallels between binge eating disorder and substance dependence highlight overlapping neurobehavioral mechanisms. As the obesity epidemic intensifies, particularly among populations with limited access to nutritious foods, understanding the pharmacological underpinnings of food addiction becomes critical. This review underscores the need to reframe UPFs as potentially addictive agents and calls for integrative therapeutic strategies and policy-driven reforms aimed at mitigating their impact on public health.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108097"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FASN targeting by G28UCM impairs mitochondrial fatty acid synthesis and reveals a FASN-SDHB Synthetic Interaction.","authors":"Nastasia Wilfinger-Lutz, Kristina M Kuehrer, Maria J Bueno, Michaela Schwaiger-Haber, Wang Wen Ann, Katrin Krejci, Ronald Mekis, Nicolle Gobbo Oliveira Erünlü, Anne Miller, Alexandra Junza, Siegfried Reipert, Michael Bergmann, Oscar Yanes, Arvand Haschemi, Gunda Koellensperger, Miguel Quintela-Fandino, Karin Nowikovsky","doi":"10.1016/j.phrs.2026.108087","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.108087","url":null,"abstract":"<p><p>Metabolic reprogramming in cancer relies on lipid synthesis and mitochondrial function, yet how these processes, other than citrate flux and β-oxidation, intersect remains unclear. While inhibitors of lipogenic pathways have been developed as potential therapeutic agents in cancer therapy, their impact on oxidative metabolism is underexplored. Here, we identify the fatty acid synthase (FASN) inhibitor G28UCM as a compound that additionally destabilizes mitochondrial fatty acid synthase (mtFAS) and succinate dehydrogenase subunit B (SDHB), thereby targeting cytosolic and mitochondrial metabolism. Unexpectedly, the decreased abundance of SDHB was linked to disruption of mtFAS, most notably downregulation of Lipoyl Synthase (LIAS). G28UCM induced profound metabolic stress, including pseudohypoxia, oxidative stress, endoplasmic reticulum stress, and ferroptosis. In contrast, genetic depletion of FASN failed to reproduce these effects. In addition to investigating the mechanism of action of G28UCM, our study revealed a genetic interaction between FASN and SDHB, establishing that their dual but not single loss of function is sufficient to impair tumor growth. The synthetic interaction was conserved across prostate cancer, neuroendocrine tumors, and renal carcinoma cell models, including patient-derived cells, and combined inhibition of FASN and SDH markedly suppressed tumor progression in a breast cancer mouse model. Our findings point to new therapeutic opportunities for FASN inhibition beyond tumor initiation, with particular relevance to cancers associated with malignant SDHB mutations.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108087"},"PeriodicalIF":10.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benefits and risks of herbal medicine use during pregnancy on offspring outcomes: A systematic review and meta-analysis of randomized controlled trials and observational studies","authors":"Chen Chen ,&nbsp;Yuezhen Li ,&nbsp;Wenling Wang ,&nbsp;Chunrong Liu ,&nbsp;Qiumei Luo ,&nbsp;Yan Ren ,&nbsp;Yiquan Xiong ,&nbsp;Xin Sun ,&nbsp;Jing Tan","doi":"10.1016/j.phrs.2026.108092","DOIUrl":"10.1016/j.phrs.2026.108092","url":null,"abstract":"<div><h3>Purpose</h3><div>Herbal medicines are widely used during pregnancy, yet their potential effects on offspring remain uncertain. This systematic review aimed to comprehensively evaluate both the potential benefits and risks of prenatal herbal medicine use on offspring outcomes by synthesizing evidence from randomized controlled trials (RCTs) and observational studies.</div></div><div><h3>Methods</h3><div>We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to November 9, 2024. Eligible studies reported maternal use of herbal medicines during pregnancy and assessed offspring-related outcomes.</div></div><div><h3>Results</h3><div>A total of 111 studies met the inclusion criteria, comprising 39 RCTs, 36 cohort studies, 18 case–control studies, and 18 cross-sectional surveys. In RCTs, prenatal use of certain herbal medicines was associated the live birth rate (RR=1.14, 95 % CI: 1.05–1.24) and a lower risk of birth defects (RR=0.46, 95 % CI: 0.22–0.94), primarily among women undergoing assisted reproduction; reductions in miscarriage were observed among those with threatened or recurrent miscarriage. At the overall level, observational studies adjusted for confounding did not show significant associations between prenatal herbal medicine use and major adverse offspring outcomes (including birth defects, miscarriage, stillbirth, or preterm birth). Exploratory analyses of individual herbal products suggested that some specific herbs—such as almond oil and <em>Glycyrrhiza</em> (with preterm birth), betel quid (with low birth weight), An-Tai-Yin (with musculoskeletal malformations), khat (with nervous system malformations), and <em>Coptidis Rhizoma</em> (with nervous system and genital organ malformations)—may be linked to increased risks. However, these signals were based on a limited number of studies and should be interpreted with caution given variability in exposure definitions, study quality, and potential residual confounding.</div></div><div><h3>Conclusions</h3><div>For women undergoing assisted reproduction or those at increased risk of miscarriage, certain herbal medicines may offer potential benefits during pregnancy. Overall, evidence from RCTs and adjusted observational studies does not indicate a clear increase in adverse offspring outcomes associated with prenatal herbal medicine use. Nonetheless, a few herbs have been linked to potential safety concerns, although the supporting evidence remains limited and heterogeneous. Cautious use is advised, particularly for products without robust data on fetal and long-term postnatal safety.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108092"},"PeriodicalIF":10.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk mechanisms among gut microbiota, novel programmed cell death, and macrophage polarization","authors":"Zilu Zhang ,&nbsp;Hewei Qin","doi":"10.1016/j.phrs.2026.108091","DOIUrl":"10.1016/j.phrs.2026.108091","url":null,"abstract":"<div><div>Several disease conditions are associated with the abnormal activation of pyroptosis, ferroptosis, necroptosis, cuproptosis, and disulfidptosis, as well as dysregulated macrophage polarization, which collectively serve as hallmarks of tissue damage and organ dysfunction. Importantly, these emerging forms of programmed cell death are closely linked to intestinal microbiota homeostasis. The gut microbiota constitutes a key ecosystem that regulates host metabolism, immunity, and overall physiological balance. When gut microbiota dysbiosis occurs, it promotes the production of harmful metabolites and activates inflammatory signaling pathways. This leads to metabolic disturbances and chronic inflammation, which in turn can induce pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and polarization of macrophages toward the M1 phenotype. Therefore, a deeper understanding of the dynamic regulation of the gut microbiota in these forms of cell death and macrophage polarization is essential for comprehending the progression of related diseases. In this review, we systematically summarize the impact of gut microbiota and its metabolite alterations on the regulation of these novel programmed cell death pathways and macrophage polarization, aiming to advance the understanding of related disease pathogenesis and provide a theoretical foundation for potential therapeutic strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108091"},"PeriodicalIF":10.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of μ-opioid receptor inhibition by orphan GPR88","authors":"Claudia Llinas del Torrent ,&nbsp;Iu Raïch ,&nbsp;Berta Carrasco-Martinez ,&nbsp;Jaume Lillo ,&nbsp;Maria Gallo ,&nbsp;David Andreu ,&nbsp;Leonardo Pardo ,&nbsp;Gemma Navarro","doi":"10.1016/j.phrs.2025.108084","DOIUrl":"10.1016/j.phrs.2025.108084","url":null,"abstract":"<div><div>From the approximately 800 members of the G protein-coupled receptor (GPCR) family, more than 100 remain orphans (oGPCRs). There is evidence indicating that some oGPCRs may carry out a physiological role independently from endogenous ligands; this includes forming heteromers with other GPCRs and altering their functional and pharmacological properties via allosteric interactions. Recent studies have shown that some of these oGPCRs, e.g. GPR88 and GPR139, allosterically inhibit opioid activity by interacting with the μ-opioid receptor (μOR). Here, we have focused on the characterization of the interaction between GPR88 and µOR and the allosteric mechanism of inhibition. We confirmed that GPR88 inhibits µOR function in striatal neuronal primary cultures. Moreover, using a peptide-interfering approach combined with biophysical and biochemical techniques, we identified that GPR88 and µOR interact via transmembrane helix 6. A combination of molecular dynamic simulations and site-directed mutagenesis have allowed to propose that the negative regulatory role of GPR88 on µOR is due to the Q298^6.49 side chain of GPR88.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108084"},"PeriodicalIF":10.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145940633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fig-derived exosome-like nanoparticles attenuating bone metastasis of breast cancer through establishing an anti-tumor microenvironment","authors":"Dan-dan Wang ,&nbsp;Jin Qian ,&nbsp;Hui-zhen Zou ,&nbsp;Hao Tian ,&nbsp;Jia Cai ,&nbsp;Cui-cui Hao ,&nbsp;Xiao-wen Huang ,&nbsp;Ming Li ,&nbsp;Yan Dai ,&nbsp;Min Zhang ,&nbsp;Gao-ming Li ,&nbsp;Song-tao Wang ,&nbsp;Meng-meng Yang ,&nbsp;Ruo-hong Liu ,&nbsp;Ce-shi Chen ,&nbsp;Xia Kang ,&nbsp;Xiao-wei Qi","doi":"10.1016/j.phrs.2026.108088","DOIUrl":"10.1016/j.phrs.2026.108088","url":null,"abstract":"<div><div>Plant-derived exosomes-like nanoparticles (ELNs) have been proven to be utilized as a promising therapy for varieties of diseases and conditions with ideal biocompatibility and biosecurity. Fig (Ficus carica) was reported to exert an anti-tumor effect, however, the active components and the underlying mechanism are still unclear. Herein, we isolated and characterized Fig-releasing ELNs (Fig-ELNs). Then, we found Fig-ELNs can prevent the growth of both human and murine breast cancer (BC) cells and induce M1 polarization of macrophages in bone metastasis murine model of BC. Mechanically, peu-miR-2916-p3 was identified as the important component in Fig-ELNs to inhibit the progression of bone metastasis of BC. Peu-miR-2916-p3 can promote the degradation of <em>RN7SL1</em> and induce the apoptosis of BC cells. On the other hand, it also directly targeted Stab1 and promote the activation of non-canonical NF-κB pathway to facilitate M1 polarization. Our study demonstrated that Fig-ELNs can be a promising therapeutical target of bone metastasis of BC through directly inhibiting the growth of BC cells and remodeling tumor microenvironment, implying as safe and effective adjuvant therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108088"},"PeriodicalIF":10.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response letter to Chi-Tung Lu et al.’s Comment on “Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China”","authors":"Yu Zhang,&nbsp;Yingjie Wang","doi":"10.1016/j.phrs.2026.108086","DOIUrl":"10.1016/j.phrs.2026.108086","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108086"},"PeriodicalIF":10.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A gut-liver lipid flux checkpoint mediates FAHFA protection from MASLD","authors":"Hao Xie ,&nbsp;Hong Sheng Cheng ,&nbsp;Jia Xun Jarryl Ng ,&nbsp;Shuang Zhang ,&nbsp;Joseph Han Sol Kim ,&nbsp;Soon Heng Tan ,&nbsp;Choon-Hong Tan ,&nbsp;Nguan Soon Tan","doi":"10.1016/j.phrs.2025.108085","DOIUrl":"10.1016/j.phrs.2025.108085","url":null,"abstract":"<div><div>Pharmacotherapies for metabolic dysfunction-associated steatotic liver disease (MASLD) remain limited. Although resmetirom and semaglutide have approvals for MASH, gut-liver axis options are still needed. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) offer anti-inflammatory and metabolic benefits but are constrained by poor stability and synthesis complexity. We develop a modular, scalable chemistry platform that installs bioisosteric linkages to generate orally stable, gut-retentive FAHFAs. High-throughput screening identifies lead candidates (12-TAASA, 12-HDTZSA) that selectively inhibit intestinal lipid handling while sparing glucose absorption. In a diet-induced MASLD model, oral dosing reduces weight gain, lowers hepatic triglycerides, improves steatosis histology and liver injury markers, and enhances glycemic control, achieving efficacy comparable to semaglutide. Mechanistically, we identify an intestine-anchored dual-brake mechanism. First, 12-TAASA slows and diminishes gut-to-liver lipid flux in vivo, directly reducing the dietary lipid burden reaching the liver. Second, 12-TAASA and 12-HDTZSA remodel the gut microbiome toward short-chain fatty acid (SCFA)–producing consortia and increase circulating, bacterially derived SCFAs, providing a complementary, microbiota-mediated route to systemic metabolic benefit. Multi-omics integration further implicates a CD44-centered epithelial program, together with allied lipid-handling pathways, as a key intestinal target network governing flux control. These findings position stabilized FAHFAs as gut-localized agents that couple epithelial lipid-uptake restraint with microbiome-derived SCFA signals to reduce gut-to-liver lipid flux, establishing an orally active, dual-action strategy for MASLD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108085"},"PeriodicalIF":10.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}