Molecular biomedicine最新文献

{"title":"The tumor suppressor NDRG2 promotes ACC1 proteasomal degradation and inhibits de novo lipogenesis in hepatocellular carcinoma.","authors":"Qianqian Shi, Yu Bai, Jiayuan Wang, Mengyao Ru, Kun Zhang, Yan Guo, Zhantao Bai, Lan Shen","doi":"10.1186/s43556-026-00451-2","DOIUrl":"10.1186/s43556-026-00451-2","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a malignant tumor characterized by high metabolic dependence. In particular, it relies on dysregulated lipid synthesis. N-myc downstream regulated gene 2 (NDRG2) acts as a tumor suppressor in HCC, yet its underlying mechanisms remain unclear. This study aimed to elucidate the role of NDRG2 in HCC progression through the regulation of lipid metabolism. We established NDRG2-overexpressing and knockout HCC cell lines, and a hepatocellular-specific Ndrg2^-/- mouse model of induced HCC. Metabolomics, Co-IP, and bioinformatics prediction were used to investigate the regulatory mechanisms and biological functions of NDRG2 on lipogenesis and the activity of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1). Interestingly, compared with wild-type mice, Ndrg2 knockout mice exhibited significantly enhanced hepatic lipogenesis and hepatocarcinogenesis. Mechanistically, NDRG2 functions as a scaffold protein that specifically recruits the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1), forming an NDRG2-COP1-ACC1 ternary complex, and thereby promoting ACC1 degradation via the ubiquitin-proteasome pathway. Furthermore, the accelerated degradation of ACC1 leads to decreases in de novo lipogenesis (DNL) and lipid droplet formation, thereby reducing the proliferation and progression of HCC cells. Notably, NDRG2-mediated ACC1 degradation significantly synergized with sorafenib to suppress tumor growth and angiogenesis. Our study revealed that NDRG2 mediates the ubiquitination and degradation of ACC1 through recruiting COP1. Thus, targeting the NDRG2-ACC1 axis or its combination with sorafenib may be a novel potential strategy for HCC therapy.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.","authors":"Mun-Ju Park, Sebin Lee, Dong-Ho Kim, Mi Kyung Kim, Byoung Kuk Jang, Ghilsuk Yoon, Mihyang Park, Gui-Hwa Jeong, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park","doi":"10.1186/s43556-026-00450-3","DOIUrl":"10.1186/s43556-026-00450-3","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains highly lethal, and emerging therapeutic strategies increasingly focus on harnessing ferroptosis to overcome treatment resistance. However, ferroptosis resistance has emerged as a major barrier to these approaches, highlighting the need to identify metabolic cues in the tumor microenvironment that drive this evasion. Here, we identify lactate as a critical metabolite that mediates detrimental metabolic crosstalk between HCC cells and hepatic stellate cells (HSCs), coupling this interaction to pyrimidine biosynthesis and enhanced extracellular matrix (ECM) production within the tumor microenvironment. We show that tumor-derived lactate activates mechanistic target of rapamycin complex 1 (mTORC1)-carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) signaling, enhancing de novo pyrimidine biosynthesis and pre-ribosomal RNA synthesis, thereby promoting ECM protein translation. The resulting ECM deposition drives Yes-associated protein (YAP)/TEA domain family member (TEAD)-dependent upregulation of the cystine/glutamate antiporter (xCT) in HCC cells, conferring marked resistance to sorafenib-induced ferroptosis. Inhibition of dihydroorotate dehydrogenase, the rate-limiting enzyme in pyrimidine synthesis, disrupts ECM production and restores ferroptosis sensitivity in vitro and in vivo. Clinical data further support these findings, indicating that phosphorylated CAD (p-CAD) levels in HSCs are associated with both poor prognosis and lactate-associated ECM enrichment in HCC patients. Collectively, our study identifies lactate-fueled pyrimidine biosynthesis as a key driver of ECM remodeling and ferroptosis resistance in HCC. Targeting this metabolic axis offers a promising therapeutic strategy to overcome ECM-mediated drug resistance and improve outcomes with ferroptosis-based HCC therapies.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13090463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.","authors":"Sara Milosevic, Eduardo Salido, Noel Mesa-Torres, Angel L Pey, Mario Cano-Muñoz","doi":"10.1186/s43556-026-00442-3","DOIUrl":"10.1186/s43556-026-00442-3","url":null,"abstract":"<p><p>Phosphorylation is a fundamental post-translational modification that contributes to the dynamic control of protein function and stability. More than 300,000 site-specific phosphorylation sites have been detected across > 20,000 human proteins, yet only a small fraction (~ 5%) have been experimentally characterized, and their roles in health and disease remain largely unexplored. In particular, the functional consequences of most phosphorylation events in metabolic enzymes remain unknown. Here, we investigated the functional impact of modifying Ser81 in alanine:glyoxylate aminotransferase (AGT), the key enzyme responsible for glyoxylate detoxification and whose loss-of-function causes Primary Hyperoxaluria Type I (PH1). We examined phosphomimetic substitutions at Ser81 in the WT (wild-type) enzyme, the common polymorphic minor allele (LM, containing two variations, p.P11L and p.I340M), and the two most frequent PH1-associated variants (LM-p.G170R and LM-p.I244T). Using biochemical, biophysical and cell-based approaches, we found that introducing a negative charge at Ser81 (through the S81D substitution) strongly perturbs PLP (pyridoxal 5´-phosphate)/PMP (pyridoxamine 5´-phosphate) binding pose and disrupts catalytic activity, while preserving secondary and tertiary structure as well as peroxisomal localization. In contrast, the non-charged S81A substitution produced milder effects. These results indicate that Ser81 contributes to stabilizing the cofactor interaction network at the AGT active site. Our findings therefore identify Ser81 as a previously uncharacterized regulatory position that can critically influence AGT activity. Although further work is required to determine the physiological frequency and regulatory context of this modification in vivo, our results suggest that phosphorylation at this position could represent an additional modulatory layer influencing AGT function and genotype-phenotype relationships in PH1, with potential implications for understanding regulatory mechanisms affecting AGT activity in disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13079258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amelioration of acute liver failure by a cinnamic acid derivative through inhibition of the ROS-NETosis axis.","authors":"Jie Yin, Longjie Ding, Ziming Zhao, Xia Chen, Jianzheng Huang, Yang Xiao, Lianghu Gu, Xiaotian Zhang, Qingyi Tong, Yonghui Zhang","doi":"10.1186/s43556-026-00448-x","DOIUrl":"10.1186/s43556-026-00448-x","url":null,"abstract":"<p><p>Acute liver failure (ALF) represents a critical clinical challenge with limited therapeutic options beyond liver transplantation, urgently requires novel therapeutic strategies. Here, we show that a cinnamic acid derivative, CA7, confers significant protection in mouse models of ALF. The therapeutic benefits of CA7 were evidenced by the preservation of hepatic architecture, reduction of mitochondrial damage and apoptosis, and enhanced survival rates. Using an integrated approach combining single-cell RNA sequencing and functional validation, we found that neutrophils are prominently involved in the hepatic response to CA7 treatment and represent a major cellular population through which CA7 exerts its protective effects. Mechanistically, CA7 exerts its potent hepatoprotective effects by selectively suppressing reactive oxygen species production, thereby inhibiting neutrophil extracellular trap formation, a pivotal trigger of hepatic oxidative injury. This intervention attenuated neutrophil recruitment and activation, restored redox homeostasis, and suppressed activation of the NF-κB-NLRP3-IL-1β inflammatory signaling cascade. As a consequence, CA7 effectively alleviated cytokine storm-associated inflammatory responses, prevented mitochondrial dysfunction and protected hepatocyte from apoptosis. Together, these coordinated actions underlie the robust protective effects of CA7 in ALF. Our findings suggest that CA7 acts as a promising therapeutic candidate for ALF and highlight reactive oxygen species (ROS)-dependent NETosis as an important pathogenic process in life-threatening ALF.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning integrated clinical-proteomics data identifies a 6-protein panel signature for atherosclerotic severity and enhanced patient stratification.","authors":"Mª Jesús Extremera-García, Marta Rojas-Torres, Blanca Priego-Torres, Lucía Beltrán-Camacho, Sara Eslava-Alcón, Francisco Rodríguez-Martín, Josefa Benítez-Camacho, Antonio Ballesteros-Ribelles, Ana Martínez Del Val, Jesper Olsen, Eva Lozano-Loaiza, Mª Ángela González-García, Daniel Sanchez-Morillo, Alejandro Fernández-Vega, Joan Montaner, Esther Doiz, Manuel Rodriguez-Piñero, Mª Carmen Durán-Ruiz","doi":"10.1186/s43556-026-00438-z","DOIUrl":"10.1186/s43556-026-00438-z","url":null,"abstract":"<p><p>Atherosclerosis, a major cause of adverse cardiovascular events and mortality rates worldwide, stems from sustained lipid accumulation and subsequent chronic inflammation within the arterial walls. An early identification of patients at risk is crucial to prevent life-threatening thrombotic events and provide effective and personalized treatments. Leveraging the power of machine learning (ML) to enhance diagnostics and biomarker discovery, we applied a high-throughput approach using five ML classification algorithms (MLCA), integrating clinical and serum proteomic data from patients with carotid atherosclerotic stenosis (AT, n:60), dyslipidemic patients (DLP, n:55), and healthy controls (HC, n:66). As a result, a robust 6-protein panel (B2M, GPV, MMP9, PLF4, TSP1, and FB isoforms) was identified with a ROC-AUC value > 0.9 for all algorithms applied, highly discriminating AT patients compared to DLP or CTRL. The levels of these proteins were further validated in an independent external cohort, including patients presenting with acute atherothrombotic stroke, corroborating the potential of this panel as biomarker for atherosclerosis severity. In addition, the combined clinical-proteomic ML approach provided a more accurate patient stratification than the clinical or proteomic analysis alone. Mechanistically, the identified biomarkers highlight the importance of platelet activation, uncontrolled angiogenesis and intraplaque haemorrhage in the atherosclerotic process, underscoring the need for multipathway therapies to prevent unwanted thrombotic events.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13069073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ANXA1/TRKA axis enhances immunotherapy sensitivity in neural invasion-positive gastric cancer.","authors":"Tianlu Jiang, Peng Zhou, Yikai Shen, Jie Lin, Ying Li, Xusheng Shen, Lang Fang, Penghui Xu, Zekuan Xu, Linjun Wang, Yiwen Xia","doi":"10.1186/s43556-026-00444-1","DOIUrl":"10.1186/s43556-026-00444-1","url":null,"abstract":"<p><p>Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide. Neural invasion (NI) is a common pathological behavior that worsens the prognosis in GC. However, the immune microenvironment of neural invasion-positive GC (NI⁺GC) and its potential therapeutic implications remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor specimens from patients with NI⁺GC and neural invasion-negative GC (NI^-GC) to comprehensively delineate the immune landscape. Our analysis revealed a significant enrichment of exhausted ANXA1⁺CD8⁺T cells within NI⁺GC tissues, which was validated by flow cytometry and multiplex immunohistochemistry assays. Clinically, patients with greater infiltration of ANXA1⁺CD8⁺ T cells had worse overall survival and disease progression. Mechanistically, ANXA1 bound to TRKA via N-terminal region, blocking NEDD4L-mediated ubiquitination and degradation of TRKA, thereby suppressing glycolytic metabolism and driving CD8⁺T cell exhaustion. Tumor-derived nerve growth factor (NGF) further amplified this exhaustion via TRKA engagement. Importantly, treatment with an ANXA1-derived peptide (A11) combined with TRKA inhibitors synergistically reversed T cell exhaustion and suppressed tumor growth in preclinical models. These findings unveil distinctive features of the immune microenvironment in NI⁺GC and elucidate the underlying molecular mechanisms of ANXA1/TRKA axis in facilitating immune evasion, which offer new insights for enhancing the sensitivity of immunotherapy to NI⁺GC patients.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the RNA-binding motif protein 15 suppresses prostate cancer progression and hormone therapy resistance by promoting androgen receptor degradation.","authors":"Bintao Hu, Le Li, Zhenghui Jin, Qinyu Li, Yue Wu, Jie Chen, Jihong Liu, Chenglin Han, Tao Wang","doi":"10.1186/s43556-026-00428-1","DOIUrl":"10.1186/s43556-026-00428-1","url":null,"abstract":"<p><p>Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkinson's disease: pathogenesis and therapeutic strategies.","authors":"Shanshan Zhang, Tingyu Wang, Ye Peng, Qianchen Wang, Zhao Zhang, Shifeng Chu, Hefei Huang, Naihong Chen","doi":"10.1186/s43556-026-00445-0","DOIUrl":"10.1186/s43556-026-00445-0","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairments such as bradykinesia, tremor, and rigidity. Its neuropathological hallmarks include the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the aggregation of α-synuclein (α-syn) into Lewy bodies (LBs), which gradually spread to other central nervous system regions and peripheral tissues. The etiology of PD is multifactorial, involving a complex interplay of genetic predisposition, aging, environmental exposures, and lifestyle factors. Disease pathogenesis is predominantly driven by the synergistic action of core pathological mechanisms, including α-syn aggregation, oxidative stress (OS), mitochondrial dysfunction, and neuroinflammation. In recent years, the role of peripheral-central communication pathways in disease initiation and propagation has garnered significant attention. To date, pharmacotherapy remains the mainstay for improving the quality of life in PD patients. The most commonly used clinical agents primarily target the replenishment of depleted dopamine in the brain. However, these medications only alleviate symptoms and do not slow disease progression. This inherent limitation underscores the urgent need for more effective therapeutic strategies. This review aims to systematically outline the network of PD pathogenesis and the evolution of its treatment strategies, with a particular emphasis on a holistic perspective from etiology to therapy. It critically evaluates current bottlenecks in drug treatment and provides an in-depth analysis of potential candidate drugs for PD, as well as the latest advances in α-syn-targeted immunotherapies, iPSC-based regenerative therapies, and gene therapies. Building on this foundation, we further argue that the future of PD management must shift towards integrated, multi-target, and personalized therapeutic strategies to overcome existing efficacy barriers.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-linear energy transfer radiation disrupts natural killer cell surveillance of senescent intestinal cells in the mouse intestine.","authors":"Santosh Kumar, Shubhankar Suman, Heng-Hong Li, Jerry Angdisen, Kamal Datta, Albert J Fornace","doi":"10.1186/s43556-026-00446-z","DOIUrl":"10.1186/s43556-026-00446-z","url":null,"abstract":"<p><p>High-Linear Energy Transfer (LET) ion radiation, such as ²⁸Si ions, is densely ionizing and poses a significant risk to astronauts during long-duration space missions. We previously showed that mice exposed to high-LET ionizing radiation (IR) exhibit greater accumulation of senescent cells in the intestine than those exposed to equivalent doses of low-LET γ-rays. However, the mechanisms driving this persistent senescence remain unclear. Given the role of Natural killer (NK) cells in senescent cell clearance, we investigated the impact of IR on intestinal NK cell function. At 60 days post-irradiation, intestinal tissues from ²⁸Si-exposed mice showed a significant reduction in NKp46⁺ NK cells and decreased expression of molecules associated with NK activation and epithelial interactions. NK cell subtype analysis further revealed a decline in functionally mature populations involved in recognizing stressed cells. In parallel, intestinal epithelial cells (IECs) displayed altered expression of NK cell regulatory ligands, including reduced activating signals and increased inhibitory signaling associated with Qa-1b (non-classical MHC class Ib). Mechanistically, these changes were linked to activation of p38 Mitogen-Activated Protein Kinase (MAPK) signaling. Using irradiated intestinal organoids, we observed that pharmacological inhibition of the p38 MAPK pathway decreased Qa-1b expression and enhanced NK cell cytotoxic activity. Causality experiments further demonstrated that Qa-1b directly regulates NK cell-mediated cytotoxicity against senescent IECs. Collectively, these findings indicate that high-LET IR compromises intestinal immune surveillance by impairing NK cell function through a p38 MAPK-Qa-1b signaling axis, providing mechanistic insight into radiation-induced immune dysregulation.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13057138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional profiling of somatostatin receptors identifies somatostatin receptor subtype 2 as a vulnerability in Succinate Dehydrogenase SDHB-deficient pheochromocytomas and paragangliomas.","authors":"Víctor García-Vioque, Sergio Pedraza-Arevalo, María Trinidad Moreno-Montilla, Esther Rivero-Cortés, Ricardo Blázquez-Encinas, Federica Mangili, Ester Arroba, Aura D Herrera-Martínez, Michael D Culler, María Ángeles Gálvez-Moreno, Anne Barlier, Luisa María Botella, Mercedes Robledo, Justo P Castaño, Alejandro Ibáñez-Costa","doi":"10.1186/s43556-026-00440-5","DOIUrl":"10.1186/s43556-026-00440-5","url":null,"abstract":"<p><p>Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20-25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST₂ agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST₂-dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST₂ and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13046876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}