Biomolecules最新文献

{"title":"Crystal Structure and Activity Analysis of <i>Chlamydophila pneumoniae</i> AP Endonuclease IV.","authors":"Jinglin Jin, Yitong Zhang, Shiyang Guo, Lihong Yang, Haixia Liu, Long Liu, Wei Gao","doi":"10.3390/biom16040594","DOIUrl":"10.3390/biom16040594","url":null,"abstract":"<p><p>DNA damage requires repair via the endonuclease IV-mediated base excision repair (BER) pathway, which corrects apurinic/apyrimidinic (AP) sites. <i>Chlamydophila pneumoniae</i> AP endonuclease IV (CpEndoIV), the sole AP endonuclease in this pathogen, is crucial for genomic integrity. As humans lack a homologous protein, it represents a potential therapeutic target. In this study, we report the first crystal structure of CpEndoIV at 1.97 Å resolution. The structure reveals two Zn²⁺, one Mg²⁺, and a malonate molecule bound in the active site, marking the first observation of Mg²⁺ coordination in the EndoIV family. Compared to the three-Zn²⁺ model with a narrow, deep pocket for precise AP-site cleavage, the Zn²⁺/Mg²⁺-bound state has a wider, shallower pocket that might promote diverse catalytic activities. Combined with enzymatic assays, we suggest that the mixed Zn²⁺/Mg²⁺ model is better adapted for CpEndoIV to operate under host oxidative stress. Malonate binds to the metal ions, occupying the positions normally coordinated by water molecules. This binding mode may mimic the coordination of the substrate to the metal ions, and the protein conformation resembles that of the enzyme upon substrate binding at the active site. This study provides a structural basis for the functional characterization of CpEndoIV and offers a reference for the development of targeted inhibitors against diseases caused by <i>Chlamydophila pneumoniae</i>.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of Baicalin in Combination with Cefotaxime on the Biofilm and Metabolic Reprogramming of Multidrug-Resistant <i>Pseudomonas aeruginosa</i>.","authors":"Xin Meng, Chao Ning, Xinyu Lu, Mengna Kang, Yuxuan Yang, Zhiyun Yu, Yu Wang, Yantong Sun, Haiyong Guo","doi":"10.3390/biom16040598","DOIUrl":"10.3390/biom16040598","url":null,"abstract":"<p><p>Baicalin, a natural plant-derived compound, holds promise in addressing clinical bacterial resistance when combined with antibiotics. This study evaluated the antibacterial activity of the combination of baicalin and cefotaxime and explored its mechanism of action on the cell wall and biofilm of multidrug-resistant <i>Pseudomonas aeruginosa</i> (MRPA). The results showed that the combination of baicalin and cefotaxime exerted a synergistic inhibitory effect on the growth of MRPA, with a fractional inhibitory concentration index (FICI) of 0.28. Mechanistically, compared with cefotaxime alone, the combination of baicalin and cefotaxime enhanced the permeability of the cell membrane and cell wall of MRPA, thereby increasing cell damage. It also exhibited stronger antibiofilm activity by inhibiting numerous virulence factors (pyocyanin, elastase, lectin), reducing cellular metabolic activity, and downregulating the expression of biofilm genes (<i>pslA</i>, <i>pelA</i>, <i>algD</i>) and quorum-sensing genes (<i>lasl</i>, <i>lasR</i>, <i>rhll</i>, <i>rhlR, pqsA, pqsR</i>). The molecular docking results revealed that baicalin could stably bind to wbpE, LasR, and RhlR. Therefore, this interaction may indirectly influence the processes related to antibiotic resistance and biofilm formation in bacterial cells. Metabolomic analysis revealed that the combination of baicalin and cefotaxime upregulated 863 metabolites and downregulated 587 metabolites. These metabolites mainly included amino acids, lipids, nucleotides, carbohydrates, and secondary metabolites. The combination primarily enriched key pathways such as amino acid metabolism, lipid metabolism (sphingolipid metabolism) and secondary metabolite biosynthesis. Through these pathways, it triggers significant metabolic reprogramming, thereby interfering with the supply of cell wall synthesis precursors, membrane structural stability, and the generation of biomembrane matrix. Ultimately, it synergistically enhances the effects of cell wall damage and biomembrane inhibition. In conclusion, this study confirms that the combination of baicalin and cefotaxime exerts significant synergistic antibacterial activity against MRPA. It also reveals the mechanism of action of the combination on the cell wall and biofilm of MRPA at the metabolic level, providing theoretical support for the development of novel strategies to combat MRPA.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetin Enhances Topotecan Cytotoxicity in Retinoblastoma Cells Through ROS-Associated Stress and Apoptotic Signaling.","authors":"Aydın Maçin, Erkan Duman, İlhan Özdemir, Mehmet Cudi Tuncer","doi":"10.3390/biom16040597","DOIUrl":"10.3390/biom16040597","url":null,"abstract":"<p><p>Quercetin, a naturally occurring flavonoid, exhibits antiproliferative and pro-apoptotic effects across various cancer models. Topotecan, a topoisomerase I inhibitor, is used in the treatment of retinoblastoma; however, its clinical utility is limited by dose-dependent toxicity. This study aimed to investigate whether quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma and to explore the underlying mechanisms under both two-dimensional (2D) and three-dimensional (3D) conditions. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) based on the Chou-Talalay method. Apoptosis was analyzed by Annexin V-FITC/PI staining and flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using fluorometric methods, and N-acetyl-L-cysteine (NAC) was used for functional modulation of oxidative stress. Three-dimensional tumor spheroid models were used to assess treatment effects under conditions that partially recapitulate tumor architecture. Gene expression levels of apoptosis-related markers and PI3K/Akt/mTOR pathway components were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The combination of quercetin and topotecan was associated with synergistic cytotoxic effects in Y79 cells (CI < 1), accompanied by increased ROS levels, mitochondrial membrane depolarization, and elevated apoptotic cell death. NAC co-treatment partially attenuated ROS levels and restored cell viability. In 3D spheroid models, combination treatment induced structural disruption, reduced viability, and increased cell death, effects that were partially reversed by NAC. Gene expression analysis revealed upregulation of pro-apoptotic genes and downregulation of survival-related genes, along with increased PTEN expression. Quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma cells under both 2D and 3D conditions. These effects were associated with ROS-associated cellular stress, mitochondrial dysfunction, and modulation of apoptotic and survival-related pathways. The partial rescue by NAC supports a contributory, but not exclusive, role of oxidative stress. These findings should be interpreted within a preclinical context and suggest that quercetin may represent a potential adjunct strategy warranting further validation in translational and in vivo models.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13115432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ezetimibe Normalizes Dietary Cholesterol-Induced Exacerbation of Liver Injury in Alcohol-Fed Mice.","authors":"Yanchao Xu, Nan Zhang, Piumi B Wickramasinghe, Kavya Veera, Preethi Parupalli, Alex Dao, Junyu Liu, Rithika Anand, Lyndsey E Langley, Sreeja Eadha, Hasan Iqbal, Chen Liu, Fang Bian, Lin Jia","doi":"10.3390/biom16040590","DOIUrl":"10.3390/biom16040590","url":null,"abstract":"<p><p>Interactions between alcohol and nutrition play an important role in the development and progression of alcohol-associated liver disease (ALD). Although dietary cholesterol was shown to exacerbate fatty liver and liver injury in alcohol-fed mice, findings regarding the combined effect of dietary cholesterol and heavy alcohol drinking on cholesterol homeostasis remain controversial. Ezetimibe has been widely used as a cholesterol-lowering drug in hypercholesterolemic subjects. It is not fully understood whether ezetimibe blunts the adverse effect of cholesterol on lipid and biliary bile acid metabolism in alcohol-exposed mice. In the current study, wild-type mice were subjected to NIAAA alcohol feeding model. Dietary cholesterol (0.2%, <i>w</i>/<i>v</i>) and ezetimibe (0.001%, <i>w</i>/<i>v</i>) were added to the liquid diets. Cholesterol and triglyceride contents in the liver and circulation were determined. Biliary bile acid composition, as well as hepatic and circulating inflammatory markers were analyzed. We found that ezetimibe protected mice from the synergistic effects of dietary cholesterol and alcohol on hepatic triglyceride accumulation, which was accompanied by enhanced expression of genes involved in hepatic beta oxidation. Dietary cholesterol caused great increases in liver cholesterol content and dramatic reductions in the expression of hepatic cholesterol biosynthetic genes in both control- and alcohol-fed mice. These changes were normalized by ezetimibe treatment. Ezetimibe attenuated dietary cholesterol-induced elevations in total biliary bile acids. Moreover, mice fed a diet containing both cholesterol and alcohol exhibited increased expression of monocyte chemoattractant protein 1 (Mcp1) and tumor necrosis factor alpha (Tnfα) in the distal small intestine. Collectively, our findings indicate that ezetimibe effectively mitigates the adverse effects of dietary cholesterol and alcohol consumption on hepatic lipid accumulation and liver injury.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Biological Profiling of New 1,2,3,4-Tetrahydrobenzo[<i>h</i>]naphthyridine-Based Hybrids as Dual Inhibitors of β-Amyloid and Tau Aggregation with Anticholinesterase Activity.","authors":"Aldrick B Verano, Anna Sampietro, Ana Mallo-Abreu, Rosaria Spagnuolo, Belén Pérez, Manuela Bartolini, María Isabel Loza, José Brea, Jordi Juárez-Jiménez, Raimon Sabate, Carles Galdeano, Diego Muñoz-Torrero","doi":"10.3390/biom16040593","DOIUrl":"10.3390/biom16040593","url":null,"abstract":"<p><p>DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids <b>16</b> and <b>17</b>, with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eicosapentaenoic Acid Attenuates Inflammation in an LPS-Induced Mouse Model of Mastitis Partly Through Modulation of the PPARγ-NF-κB Signaling Pathway.","authors":"Zhiwei Duan, Ting Lu, Kejiang Liu, Xiaoxuan Zhao, Wenkai Bai, Bohao Zhang, Quanwei Zhang, Xingxu Zhao, Weitao Dong, Yong Zhang","doi":"10.3390/biom16040592","DOIUrl":"10.3390/biom16040592","url":null,"abstract":"<p><p>Mastitis is a common inflammatory disease that harms mammary gland health. Its development is closely linked to dysregulated inflammatory signaling. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, has potential anti-inflammatory effects. However, its molecular mechanism in mastitis prevention remains unclear. In this study, we used both in vivo and in vitro models to evaluate how EPA pretreatment regulates mastitis-related inflammatory signaling. Transcriptome analysis showed that differentially expressed genes after EPA treatment were mainly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In an LPS-induced mastitis model, EPA restored the LPS-reduced PPARγ protein level and suppressed NF-κB p65 activation, consistent with reduced nuclear translocation of p65. Similar effects were observed in mammary epithelial cells, where EPA inhibited NF-κB activation at 50 and 100 μM. Functional experiments further showed that a PPARγ agonist mimicked the inhibitory effect of EPA on p65, whereas PPARγ antagonist partially abrogated EPA-mediated inhibition of p65. Collectively, these data indicate that EPA attenuates mastitis-associated inflammation at least in part through the PPARγ-NF-κB axis.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13115396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico Drug Design and Discovery: Big Data for Small Molecule Design-2nd Edition.","authors":"Carmen Cerchia, Antonio Lavecchia","doi":"10.3390/biom16040591","DOIUrl":"10.3390/biom16040591","url":null,"abstract":"<p><p>The volume and heterogeneity of data available to drug discovery have grown at a pace that would have been difficult to predict even a few years ago [...].</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galectin-3 Binds to the Allosteric Site and Activates Integrins αvβ3, αIIbβ3, and α5β1, and Lactose Inhibits This Activation.","authors":"Yoko K Takada, Yu-Jui Yvonne Wan, Yoshikazu Takada","doi":"10.3390/biom16040586","DOIUrl":"10.3390/biom16040586","url":null,"abstract":"<p><p>Galectin-3 (Gal3) is one of the most pro-inflammatory proteins and a biomarker of inflammatory diseases and cancer. Previous studies showed that Gal3 binds to αv and β1 integrins, but it is unclear how Gal3 binds to integrins. Here, we show that Gal3 bound to soluble αvβ3 and αIIbβ3 integrins in 1 mM Mn²⁺ in cell-free conditions in a glycan-independent manner. Docking simulation predicts that Gal3 binds to the classical RGD-binding site (site 1) of αvβ3, but the predicted Gal3-binding site does not include galactose-binding site. RGDfV or eptifibatide inhibited Gal3 binding to αvβ3 and αIIbβ3, respectively, but lactose, a pan-galectin inhibitor, did not inhibit Gal3 binding to integrins. Point mutations of the predicted site 1 binding interface of Gal3 effectively inhibited Gal3 binding to site 1. Site 2 is involved in pro-inflammatory signaling (e.g., TNF and IL-6 secretion), and we previously showed that pro-inflammatory cytokines (e.g., CCL5 and TNF) bind to site 2 and allosteric integrin activation. Docking simulation predicted that Gal3 binds to site 2 of αvβ3 and α5β1. We found that Gal3 induced allosteric activation of soluble integrins αvβ3, αIIbβ3, and α5β1 in 1 mM Ca²⁺ in cell-free conditions. Point mutations in the predicted site 2 binding interface inhibited Gal3-induced integrin activation, suggesting that Gal3 binding to site 2 is required for Gal3-induced integrin activation. Known anti-inflammatory agents, Ivermectin, NRG1, and FGF1, inhibited integrin activation induced by Gal3 in αvβ3 and αIIbβ3. These findings suggest that Gal3 binding to site 2 may be a potential mechanism of pro-inflammatory and pro-thrombotic action of Gal3.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Biomarkers for Predicting Nucleoside Analog Drug Response and Resistance in Cancer.","authors":"John Kaszycki, Jackson C Lin, Minji Kim, Hunmin Jung","doi":"10.3390/biom16040587","DOIUrl":"10.3390/biom16040587","url":null,"abstract":"<p><p>Nucleoside analogs (NAs) play a central role in cancer therapy, either through direct cytotoxicity or epigenome reprogramming. They are clinically effective but have shortcomings in their long-term effectiveness because of variable patient responses and the emergence of resistance. There is growing evidence that DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs) are key factors that determine sensitivity and resistance to NAs. This review summarizes existing evidence on the epigenetic control of cytotoxic and epigenetic nucleoside analogs, discusses predictive biomarkers of human Equilibrative Nucleoside Transporter 1 (hENT1) and deoxycytidine kinase (dCK) promoter methylation, histone modifications, and ncRNA signatures, and assesses the emerging strategies of multi-omic integration. Improvements in detection methods, such as high-resolution sequencing, single-cell profiling, and liquid biopsy, are addressed, along with the issues of reproducibility, tumor heterogeneity, and clinical translation. Epigenetic biomarkers are promising for patient stratification in clinical trials, although a lack of uniformity in technical and methodological approaches currently constrains their full potential. The future focus will be on standardized panels of biomarkers, real-time monitoring, rational combination strategies, and biomarker-directed clinical trial designs. Overall, epigenetic biomarkers are capable of changing nucleoside analog therapy into a more precise, durable, and personalized treatment approach.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterotopic Ossification: Molecular Drivers, Subtype-Specific Mechanisms, and Translational Therapeutic Advances.","authors":"Sihong Chen, Hui Lin","doi":"10.3390/biom16040585","DOIUrl":"10.3390/biom16040585","url":null,"abstract":"<p><p>Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor-beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}