Zuhui Liang, Yingyi Ye, Zhihong Deng, Huan Lan, Caihong Liu, Yuanhang Xu, Minqi Fan, Zhongqiu Liu, Peng Wu, Lin An, Caiyan Wang
{"title":"CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent in hepatocellular carcinoma.","authors":"Zuhui Liang, Yingyi Ye, Zhihong Deng, Huan Lan, Caihong Liu, Yuanhang Xu, Minqi Fan, Zhongqiu Liu, Peng Wu, Lin An, Caiyan Wang","doi":"10.1016/j.phrs.2025.107698","DOIUrl":"https://doi.org/10.1016/j.phrs.2025.107698","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) was associated with high morbidity and mortality, representing a significant health challenge. Chondroitin sulfate (CS), a glycosaminoglycan composed of glucuronic acid and N-acetylgalactosamine, is implicated in HCC progression through its role in cancer cell migration and proliferation as well as interactions with cell surface receptors integrin β-1 and CD44. Chondroitin polymerization factor 2 (CHPF2), the key to CS synthesis, has an undefined role in HCC. Our study aims to demonstrate that decreasing CHPF2 enzyme activity can inhibit the migration and proliferation of HCC cells. Bioinformatics analysis and in vitro experiments on clinical HCC samples confirmed the knockdown of CHPF2 inhibited HCC cell proliferation and migration. We further explored Rabdosia rubescens, a plant used in cancer therapy, for its potential to modulate CHPF2. Structural biology and ligand fishing identified ponicidin, a compound that significantly suppresses HCC cell growth and migration in both in vitro and in vivo models. These findings propose CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent for HCC management.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107698"},"PeriodicalIF":9.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664183","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}
Eda Koseli, Belle Buzzi, Torin Honaker, Yogesh Rakholia, Melissa Lewis, Maya Gaines-Smith, Alaina M Jaster, Javier Gonzalez-Maeso, M Imad Damaj
{"title":"IUPHAR Article: Psilocybin induces long-lasting effects via 5-HT<sub>2A</sub> receptors in mouse models of chronic pain.","authors":"Eda Koseli, Belle Buzzi, Torin Honaker, Yogesh Rakholia, Melissa Lewis, Maya Gaines-Smith, Alaina M Jaster, Javier Gonzalez-Maeso, M Imad Damaj","doi":"10.1016/j.phrs.2025.107699","DOIUrl":"https://doi.org/10.1016/j.phrs.2025.107699","url":null,"abstract":"<p><p>Chronic pain is a debilitating disease with current treatments lacking efficacy and safety, therefore discovery of new treatments is crucial. Initial studies suggest that psychedelics may be feasible for targeting pain, however clinical and preclinical controlled studies are necessary to further investigate that possibility. In this study we assessed the effects of two classical psychedelics psilocybin and 2,5-Dimethoxy-4-iodoamphetamine (DOI) in two models of chronic pain after systemic administration in male and female mice. Psilocybin and DOI dose-dependently reversed mechanical and cold hypersensitivity in the chemotherapy-induced peripheral neuropathy (CIPN) mouse model with different time-course of action. Similarly, psilocybin and DOI dose-dependently reversed thermal hypersensitivity in the chronic inflammatory mouse model of Complete Freud's Adjuvant (CFA). The effects of Psilocybin and DOI in both models were mediated by activation of 5-HT<sub>2A</sub> receptors (5-HT<sub>2A</sub>R). Overall, the present study suggests that classical psychedelics psilocybin and DOI are effective in reducing pain-like behaviors via 5-HT<sub>2A</sub>R activation in two mouse models of chronic pain.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107699"},"PeriodicalIF":9.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664185","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}
Chenyang Wang , Shun Wan , Kunpeng Li , Siyu Chen , Yuncong Shu , Shanhui Liu , Li Yang
{"title":"TPI1 promotes p53 ubiquitination in bladder cancer by recruiting AKT to enhance MDM2 phosphorylation","authors":"Chenyang Wang , Shun Wan , Kunpeng Li , Siyu Chen , Yuncong Shu , Shanhui Liu , Li Yang","doi":"10.1016/j.phrs.2025.107695","DOIUrl":"10.1016/j.phrs.2025.107695","url":null,"abstract":"<div><div>Bladder cancer (BCa) is an aggressive malignancy with limited effective treatment options, and its poor outcomes largely result from delayed detection and therapeutic resistance. Triosephosphate isomerase 1 (<em>TPI1</em>) has been associated with tumor progression in various cancers, but its specific function in BCa remains poorly characterized. This study evaluated cancer-related markers and identified glycolysis as a key factor negatively impacting survival in BCa. Additionally, <em>TPI1</em> was recognized as a potential prognostic marker, with its expression significantly elevated in BCa tissues compared to normal counterparts. Higher <em>TPI1</em> levels were strongly linked to unfavorable clinical outcomes. Functional assays demonstrated that <em>TPI1</em> overexpression significantly promoted BCa cell growth, migration, and invasive capabilities <em>in vitro</em> and <em>in vivo</em>. Mechanistically, <em>TPI1</em> interacted with serine/threonine kinase B (<em>AKT</em>) and murine double minute 2 (<em>MDM2</em>) to form a protein complex, which enhanced the <em>AKT</em>-driven phosphorylation of <em>MDM2</em> at serine 166 site, thereby promoting tumor protein p53 (<em>p53</em>) ubiquitination degradation. Furthermore, the truncated <em>MDM2</em>-F2 mutant (spanning 181–360) bound to <em>TPI1</em>, with amino acid 317 playing a critical role in this interaction. Notably, reducing <em>AKT</em> expression counteracted the <em>p53</em> ubiquitination triggered by elevated <em>TPI1</em>.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107695"},"PeriodicalIF":9.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143644656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vishnu Sravan Bollu, Yu-Chi Chen, Fan Zhang, Krishne Gowda, Shantu Amin, Arun K Sharma, Todd D Schell, Jiyue Zhu, Gavin P Robertson
{"title":"Managing Telomerase and Telomere Dysfunction in Acral Melanoma.","authors":"Vishnu Sravan Bollu, Yu-Chi Chen, Fan Zhang, Krishne Gowda, Shantu Amin, Arun K Sharma, Todd D Schell, Jiyue Zhu, Gavin P Robertson","doi":"10.1016/j.phrs.2025.107700","DOIUrl":"https://doi.org/10.1016/j.phrs.2025.107700","url":null,"abstract":"<p><p>Acral Lentiginous Melanoma is a rare and aggressive subtype of melanoma that commonly affects the palms, soles, and nail beds. It is more prevalent in individuals with darker skin tones, including Asian, African, and Hispanic populations. Unlike cutaneous melanomas, acral melanoma is not associated with UV exposure and has a distinct genetic and molecular profile, underscoring the need for tailored research and treatment strategies. Standard treatments, such as surgery, chemotherapy, immunotherapy, and targeted therapies, have shown limited success for this melanoma subtype, highlighting the urgency of developing more effective interventions. Telomerase is an enzyme that extends telomeres and is a key target in acral melanoma which exhibits' high telomerase activity, driven by mutations in the telomerase reverse transcriptase TERT promoter, which contributes to uncontrolled tumor cell proliferation, cancer cell immortality, and resistance to conventional therapies. Therefore, targeting telomerase presents a promising therapeutic avenue for acral melanoma patients who do not respond well to current treatments. Several approaches for targeting telomerase deregulation have been developed, and their potential for the management of acral melanoma is discussed in this review. Specifically, the promise of telomerase-targeted therapies for acral melanoma is emphasized and explores how these strategies could improve outcomes for patients with this challenging skin cancer. By focusing on the role of telomerase in tumorigenesis and treatment resistance, telomerase-targeted strategies hold potential as a foundational component of therapies for acral melanoma, complementing existing approaches.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107700"},"PeriodicalIF":9.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649958","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":"Corrigendum to “The essential role of sphingolipids in TRPC5 ion channel localization and functionality within lipid rafts” [Pharmacol. Res. (2025) 213 107648]","authors":"Junliang Wan, Jingjing Duan","doi":"10.1016/j.phrs.2025.107692","DOIUrl":"10.1016/j.phrs.2025.107692","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107692"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wan-Yi Guo , Qi-Min Wu , Hao-Feng Zeng , Yu-Lian Chen , Jie Xu , Zhen-Yi Yu , Yong-Kang Shu , Xiao-Nan Yang , Chuan-Hai Zhang , Xi-Zi He , Jia-Ning Mi , Si Chen , Xiao-Man Chen , Jia-Qi Wu , He-Quan Yao , Liang Liu , Hu-Dan Pan
{"title":"A sinomenine derivative alleviates bone destruction in collagen-induced arthritis mice by suppressing mitochondrial dysfunction and oxidative stress via the NRF2/HO-1/NQO1 signaling pathway","authors":"Wan-Yi Guo , Qi-Min Wu , Hao-Feng Zeng , Yu-Lian Chen , Jie Xu , Zhen-Yi Yu , Yong-Kang Shu , Xiao-Nan Yang , Chuan-Hai Zhang , Xi-Zi He , Jia-Ning Mi , Si Chen , Xiao-Man Chen , Jia-Qi Wu , He-Quan Yao , Liang Liu , Hu-Dan Pan","doi":"10.1016/j.phrs.2025.107686","DOIUrl":"10.1016/j.phrs.2025.107686","url":null,"abstract":"<div><div>Bone destruction in rheumatoid arthritis (RA) leads to significant disability, yet effective treatments are limited. Sinomenine (Sino) demonstrates anti-arthritic and bone-protective effects but requires high doses. In this study, we developed a Sino derivative, SINX, and evaluated its efficacy in RA. Safety assessments in mice confirmed its suitability for further study. <em>In vitro</em>, SINX inhibited osteoclast differentiation by reducing TRAP-positive cells, disrupting F-actin ring formation, and suppressing bone resorption pits, alongside downregulating osteoclast-specific genes. It also showed strong anti-inflammatory properties by reducing inflammatory cytokine levels. <em>In vivo</em>, using a collagen-induced arthritis (CIA) mouse model, SINX improved bone integrity by reducing joint inflammation, maintaining trabecular bone density, and preventing erosion. Histological and micro-CT analyses confirmed its effects, including suppressed osteoclast activity and reduced bone resorption-related gene expression. Mechanistically, SINX ameliorated mitochondrial dysfunction, decreased ROS levels, and activated the NRF2/HO-1/NQO1 pathway, enhancing antioxidant defenses. Compared to Sino, SINX achieved similar results at lower doses. These findings highlight the potential of SINX as a safe, effective treatment for RA-related bone destruction.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107686"},"PeriodicalIF":9.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher Douglas, Shashi Jain, Naomi Lomeli, Javier Lepe, Kaijun Di, Nitesh Kumar Nandwana, Adil Shareef Mohammed, Thao Vu, James Pham, Maria Cristina Kenney, Bhaskar Das, Daniela A Bota
{"title":"Dual targeting of the mitochondrial Lon peptidase 1 and the chymotrypsin-like proteasome activity as a potential therapeutic strategy in malignant astrocytoma models.","authors":"Christopher Douglas, Shashi Jain, Naomi Lomeli, Javier Lepe, Kaijun Di, Nitesh Kumar Nandwana, Adil Shareef Mohammed, Thao Vu, James Pham, Maria Cristina Kenney, Bhaskar Das, Daniela A Bota","doi":"10.1016/j.phrs.2025.107697","DOIUrl":"10.1016/j.phrs.2025.107697","url":null,"abstract":"<p><p>Malignant astrocytomas are aggressive primary brain tumors characterized by extensive hypoxia-induced, mitochondria-dependent changes such as altered respiration, increased chymotrypsin-like (CT-L) proteasome activity, decreased apoptosis, drug resistance, stemness, and increased invasiveness. Mitochondrial Lon Peptidase 1 (LonP1) overexpression and increased CT-L proteasome activity are biomarkers of an aggressive high-grade phenotype and found to be associated with recurrence and poor patient survival. In preclinical models, small molecule agents targeting either LonP1 or the proteasome CT-L activity have anti-astrocytoma activity. Here, we present evidence that the dual inhibition of LonP1 and CT-L proteasome activity effectively induces ROS production, leading to apoptosis in malignant astrocytoma established cell lines and patient-derived glioma stem cell-like cultures. We also evaluated a novel small molecule, BT317, derived from the coumarinic compound 4 (CC4) using structure-activity modeling, which we found to inhibit both LonP1 and CT-L proteasome activity. Using gain- and loss-of-function genetic models, we discovered that LonP1 is both necessary and sufficient to drive BT317 drug sensitivity in established and patient-derived glioma stem-like cells by generating ROS and inducing apoptosis. In vitro, BT317 had activity as a single agent but, more importantly, enhanced synergy with the standard of care commonly used chemotherapeutic temozolomide (TMZ). In an orthotopic xenograft astrocytoma model, BT317 crossed the blood-brain barrier, showed selective activity at the tumor site, and demonstrated therapeutic efficacy as a single agent and combined with TMZ. BT317 defines an emerging class of LonP1 and CT-L inhibitors that exhibited promising anti-tumor activity and could be a potential candidate for malignant astrocytoma therapeutics. SIMPLE SUMMARY: Malignant astrocytoma patients have poor clinical outcomes, and novel treatments are needed to limit tumor recurrence and improve their overall survival. These tumors have a malignant phenotype mediated by altered mitochondrial metabolism, abnormal protein processing, and adaptation to hypoxia. We have previously published that astrocytomas are especially vulnerable to proteasome inhibitors as well as to inhibitors of the mitochondrial Lon Peptidase 1 (LonP1), but the effect of combining the two strategies has not been reported. Here, we present evidence that the dual inhibition of LonP1 and Chymotrypsin-like (CT-L) proteasome activity effectively induces cellular reactive oxygen species (ROS) production, leading to apoptosis in malignant astrocytoma established cell lines and patient-derived glioma stem cell-like cultures. We developed BT317, a small molecule dual inhibitor, which crosses the blood-brain barrier and shows strong synergy with the standard of care, temozolomide (TMZ), in the astrocytoma cell lines independent of their isocitrate dehydrogenase (IDH) profile and in an or","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107697"},"PeriodicalIF":9.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634405","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":"From Gut to Brain: The Role of Gut Dysbiosis, Bacterial Amyloids, and Metabolic Disease in Alzheimer's Disease.","authors":"Saadet Inan, R Paul Wilson, Çagla Tükel","doi":"10.1016/j.phrs.2025.107693","DOIUrl":"https://doi.org/10.1016/j.phrs.2025.107693","url":null,"abstract":"<p><p>Gut microbial dysbiosis, or altered gut microbial communities, in Alzheimer's Disease suggests a pathogenic role for gut inflammation and microbial products in shaping a neuroinflammatory environment. Similarly, metabolic diseases, such as obesity and diabetes, are also associated with an increased risk of Alzheimer's Disease. As the metabolic landscape shifts during gut inflammation, and gut inflammation in turn impacts metabolic processes, we explore how these interconnected pathways may contribute to the progression of Alzheimer's Disease. Additionally, we discuss the role of bacterial amyloids produced by gut microbes, which may exacerbate amyloid aggregation in the brain and contribute to neurodegenerative processes. Furthermore, we highlight potential therapeutic strategies aimed at reducing gut inflammation, improving metabolic health, and decreasing amyloid content as a means to mitigate Alzheimer's Disease progression. These approaches, targeting the gut-brain-metabolic axis, could offer promising avenues for delaying or preventing cognitive decline in affected individuals.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107693"},"PeriodicalIF":9.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630920","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}
Veronica Begni , Alessia Marchesin , Marco Andrea Riva
{"title":"IUPHAR review – Novel therapeutic targets for schizophrenia treatment: A translational perspective","authors":"Veronica Begni , Alessia Marchesin , Marco Andrea Riva","doi":"10.1016/j.phrs.2025.107690","DOIUrl":"10.1016/j.phrs.2025.107690","url":null,"abstract":"<div><div>Schizophrenia is a severe and debilitating psychiatric disorder that profoundly impacts cognitive, emotional, and social functioning. Despite its devastating personal and societal toll, current treatments often provide only partial relief, underscoring the urgent need for innovative therapeutic strategies. This review explores emerging approaches that target the complex neurobiological underpinnings of schizophrenia, moving beyond traditional dopamine-centric models. Among these, some novel drugs still employ multimodal mechanisms, simultaneously targeting dopaminergic and serotonergic systems to enhance efficacy and tolerability. Given the well-documented excitatory/inhibitory imbalance in schizophrenia, significant efforts have been directed toward addressing NMDA receptor hypofunctionality. However, strategies targeting this pathway have yet to demonstrate consistent clinical efficacy. In contrast, therapies targeting the cholinergic system have shown greater promise. For instance, the xanomeline-trospium combination, which modulates muscarinic receptors, has recently gained approval, and other molecules with similar mechanisms are currently under development. Beyond these approaches, novel strategies are being explored to target innovative pathways, including neuroplasticity, neuroinflammation, and mitochondrial dysfunction. These efforts are often designed as part of a combinatorial strategy to enhance the efficacy of currently available antipsychotic drugs. Despite significant progress, challenges remain in translating experimental discoveries into effective clinical applications. Future research should prioritize biomarker-driven approaches and precision medicine to optimize individualized treatment outcomes. By integrating these emerging therapeutic targets, schizophrenia treatment may evolve toward a more comprehensive and personalized approach, addressing the disorder’s full spectrum of symptoms and improving patient quality of life.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107690"},"PeriodicalIF":9.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Min You , Li Zhou , Fan Wu , Lei Zhang , Shu-xiu Zhu , Hong-xing Zhang
{"title":"Probiotics for the treatment of hyperlipidemia: Focus on gut-liver axis and lipid metabolism","authors":"Min You , Li Zhou , Fan Wu , Lei Zhang , Shu-xiu Zhu , Hong-xing Zhang","doi":"10.1016/j.phrs.2025.107694","DOIUrl":"10.1016/j.phrs.2025.107694","url":null,"abstract":"<div><div>Hyperlipidemia, a metabolic disorder marked by dysregulated lipid metabolism, is a key contributor to the onset and progression of various chronic diseases. Maintaining normal lipid metabolism is critical for health, as disruptions lead to dyslipidemia. The gut and liver play central roles in lipid homeostasis, with their bidirectional communication, known as the gut-liver axis, modulated by bile acids (BAs), gut microbiota, and their metabolites. BAs are essential for regulating their own synthesis, lipid metabolism, and anti-inflammatory responses, primarily through the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Available evidence suggests that high-fat diet-induced the gut microbiota dysbiosis can induce \"leaky gut,\" allowing toxic microbial metabolites to enter the liver <em>via</em> portal circulation, triggering liver inflammation and lipid metabolism disturbances, ultimately leading to hyperlipidemia. Extensive studies have highlighted the roles of probiotics and Traditional Chinese Medicine (TCM) in restoring gut-liver axis balance and modulating lipid metabolism through regulating the levels of lipopolysaccharides, short-chain fatty acids, and BAs. However, the therapeutic potential of probiotics and TCM for hyperlipidemia remains unclear. Here, firstly, we explore the intricate interplay among gut microbiota and metabolites, lipid metabolism, gut-liver axis, and hyperlipidemia. Secondly, we summarize the mechanisms by which probiotics and TCM can alleviate hyperlipidemia by altering the composition of gut microbiota and regulating lipid metabolism via the gut-liver axis. Finally, we emphasize that more clinical trials of probiotics and TCM are necessary to examine their effects on lipid metabolism and hyperlipidemia.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"214 ","pages":"Article 107694"},"PeriodicalIF":9.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143593333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}