Biomolecules & Therapeutics最新文献

{"title":"Artificial Intelligence in Mass Spectrometry-Based Metabolomics and Lipidomics for Drug Discovery and Development.","authors":"Young Cheol Yoon, Seoyeon Choi, Cheol Woon Jung, Hendra Mahakam Putra, Young Jin Min, Sun Jo Kim, Sung Won Kwon","doi":"10.4062/biomolther.2026.225","DOIUrl":"10.4062/biomolther.2026.225","url":null,"abstract":"<p><p>Artificial intelligence applied to mass spectrometry-based metabolomics and lipidomics has advanced through three technological generations: chemometric and classical machine learning, deep learning, and self-supervised foundation models, with large language models so far entering mainly at the edges. The metabolome and lipidome lie closest to drug action, yet they have been among the slowest omics layers to adopt modern artificial intelligence. This paradox arises from their downstream position, which leaves them without a closed molecular reference and without the standardized, readily modeled data available to the genome and transcriptome. This review examines what these methods contribute to drug discovery and development. We survey applications across the drug-development pipeline, from target identification and mechanism of action deconvolution, through the prediction of drug-induced toxicity, to pharmacometabolomics, in which pre-dose metabolic phenotypes inform patient stratification and dosing. Across these metabolomic and lipidomic applications, interpretable classical machine learning remains the dominant form of artificial intelligence. The newer deep-learning and foundation models have concentrated instead on compound annotation, the cross-cutting problem of assigning confident identities to spectra, yet successive generations have mitigated but not solved it. Beyond annotation confidence, batch effects, semi-quantification, and small-cohort overfitting also remain practical constraints. Overall, targeted, hypothesis-driven metabolomic and lipidomic studies can already support drug discovery when their inferences are restricted to confidently identified metabolites, whereas open, hypothesis-free discovery remains the frontier. Near-term progress will depend less on any single algorithm than on curated spectral resources, rigorous measurement, leakage-aware validation, and honest reporting of identification confidence.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"1368-1384"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13724998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"6-Hydroxyrubiadin Regulates TNF-α-Induced MUC5AC Gene Expression via Affecting NF-κB and MAPK Signaling Pathways in Human Airway Epithelial Cells.","authors":"Rajib Hossain, MinKyun Na, Md Solayman Hossain, Sainan Li, Hyun Jae Lee, Gang Min Hur, Choong Jae Lee","doi":"10.4062/biomolther.2026.187","DOIUrl":"10.4062/biomolther.2026.187","url":null,"abstract":"<p><p>In this study, we aimed to investigate whether 6-hydroxyrubiadin (6-HR), a compound derived from the root of <i>Rubia akane</i> Nakai, exerts a regulatory effect on the gene expression of MUC5AC mucin under conditions mimicking pulmonary inflammation in human airway epithelial cells. Confluent NCI-H292 cells were pretreated with 6-HR for 30 min, followed by stimulation with tumor necrosis factor (TNF)-α for 24 h. MUC5AC mRNA expression and glycoprotein production were measured using reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Further, we examined the effect of 6-HR on TNF-α-induced activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways via immunoblot analysis. The results were as follows: (1) 6-HR significantly reduced both the production of MUC5AC glycoprotein and MUC5AC mRNA expression in NCI-H292 cells. (2) 6-HR inhibited TNF-α-induced NF-κB activation through a transforming growth factor-β-activated kinase 1 (TAK1)-dependent mechanism. (3) 6-HR also inhibited TAK1-dependent MAPK signaling pathways activated by TNF-α, resulting in the downregulation of MUC5AC mucin production in NCI-H292 cells. These findings suggest that 6-HR regulates the gene expression of MUC5AC mucin by directly acting on airway epithelial cells through modulation of the MAPK and NF-κB signaling pathways.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1385-1393"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13724999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2 Activation Induces Fibroblast Senescence and Promotes Melanosome Accumulation in a Fibroblast-Keratinocyte Co-Culture Model.","authors":"Ji Hye Yoon, In Seop Kil, Siyoung Cho, Sunyoung Park, Hyung-Su Kim, Ji Hye Kim, Jae Youl Cho","doi":"10.4062/biomolther.2026.104","DOIUrl":"10.4062/biomolther.2026.104","url":null,"abstract":"<p><p>Solar lentigo (SL) is an age-associated hyperpigmented skin disorder linked to oxidative stress, impaired autophagy, and cellular senescence. However, experimental systems that recapitulate the senescence-associated skin microenvironment remain limited. In this study, we investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in fibroblast senescence and pigmentation-related responses using transcriptomic analyses and a fibroblast-keratinocyte co-culture model. Public transcriptomic datasets revealed increased NFE2L2 expression together with altered autophagy-related and senescence-associated signatures in hyperpigmented skin lesions. In dermal fibroblasts, Nrf2 overexpression induced senescence-associated phenotypes, including increased SA-β-gal activity and elevated expression of SASP-related genes. In a fibroblast-keratinocyte co-culture system, Nrf2-activated fibroblasts promoted melanosome accumulation in keratinocytes, suggesting that senescence-associated dermal-epidermal interactions contribute to pigmentation-related alterations. SENOMUNE, a formulation with autophagy-modulating activity, enhanced LC3 puncta formation in keratinocytes and attenuated melanosome accumulation in the senescence-associated co-culture system. Collectively, these findings suggest that sustained Nrf2 activation contributes to fibroblast senescence and pigmentation-related responses and provide a useful co-culture platform for evaluating senescence-associated pigmentation modulators.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1456-1471"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149285045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WNT5A-Associated Osteogenic Enhancement Contributes to the Protective Effects of OPG-Fc in Glucocorticoid-Associated Femoral Head Osteonecrosis.","authors":"Wei Shi, Zeyu Dai, Chaobo Li, Yongqing Xu","doi":"10.4062/biomolther.2026.087","DOIUrl":"10.4062/biomolther.2026.087","url":null,"abstract":"<p><p>Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive orthopedic disorder characterized by an imbalance between bone resorption and bone formation. Although receptor activator of nuclear factor kappa-B ligand (RANKL) blockers are known to suppress osteoclast activity, whether they also promote osteogenesis and the underlying molecular mechanisms remain poorly understood. In this study, we investigated whether osteoprotegerin-Fc (OPG-Fc) exerts osteoprotective effects in SONFH and whether wingless-type MMTV integration site family, member 5A (WNT5A) signaling is involved. A rat SONFH model was established using lipopolysaccharide (LPS) combined with methylprednisolone sodium succinate (MPS), and bone marrow mesenchymal stem cells (BMSCs) were cultured under glucocorticoid-containing conditions. OPG-Fc, the WNT5A antagonist box5, and Wnt5a knockdown were used, and analyses included micro-computed tomography (micro-CT), histological staining, transcriptome sequencing, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting. Our results demonstrated that OPG-Fc significantly improved bone trabecular microarchitecture, reduced empty lacunae and tartrate-resistant acid phosphatase (TRAP)-positive cells, and increased cartilage thickness <i>in vivo</i>. <i>In vitro</i>, OPG-Fc promoted osteogenic differentiation while inhibiting adipogenic differentiation of BMSCs. Transcriptome and protein analyses revealed significantly higher WNT5A expression following OPG-Fc treatment. Importantly, pharmacological blockade of WNT5A with box5 and Wnt5a knockdown partially attenuated OPG-Fc-associated pro-osteogenic effects, whereas box5 had limited effects on anti-resorptive marker changes. These findings suggest that OPG-Fc exerts dual protective actions in SONFH by suppressing bone resorption and enhancing osteogenic differentiation in association with WNT5A-related signaling. This study provides new mechanistic insights into RANKL blockade therapy and offers a potential molecular target for early intervention in SONFH.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1424-1440"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-Enabled Animal Behavior Analysis for Translational Pharmacology and Therapeutic Discovery.","authors":"Sunwhi Kim","doi":"10.4062/biomolther.2026.157","DOIUrl":"10.4062/biomolther.2026.157","url":null,"abstract":"<p><p>Animal behavior is a critical endpoint in preclinical pharmacology, toxicology, and therapeutic discovery, yet conventional behavioral scoring remains labor-intensive, low-dimensional, and difficult to reproduce across laboratories. Artificial intelligence (AI) can now quantify behavior from video with greater spatial, temporal, and phenotypic resolution. This review summarizes how object detection, markerless pose estimation, unsupervised behavioral segmentation, foundation models, and autonomous analysis agents are reshaping behavioral phenotyping. General-purpose object detectors rapidly localize and track animals, whereas open-source pose-estimation tools extend measurement beyond centroid tracking to body-part trajectories and fine motor patterns; paired with supervised classifiers, they have matched human scoring and exceeded some commercial systems. Technical accuracy alone does not establish behavioral construct validity or pharmacological validity. Unsupervised methods such as Motion Sequencing represent drug responses and disease-model phenotypes as structured changes in behavioral states rather than only as predefined endpoints, providing high-dimensional fingerprints of pharmacological action. Segmentation and tracking foundation models may reduce annotation burden but require validation across species, strain, sex, apparatus, and paradigm. AI agents may assist with literature review, code generation, analysis auditing, and figure production but must remain within transparent, human-supervised workflows. In behavioral pharmacology, pose estimation is established as a measurement method and emerging as a drug-effect endpoint, supervised classification and unsupervised segmentation are emerging, and foundation models and agents remain prospective. AI-enabled behavioral analysis can become a reproducible phenotyping layer for drug discovery and toxicology if researchers adopt open pipelines, rigorous validation, and reporting standards, rather than replacing one opaque measurement system with another.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1331-1349"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13724995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenine Promotes Osteogenic Differentiation and Suppresses Osteoclastogenesis.","authors":"RanJu Woo, Chang Seon Ryu, Doyoung Kwon, Sou Hyun Kim, Ki Wung Chung, Jaewon Lee, Keuk-Jun Kim, Yun-Hee Lee, Young-Suk Jung","doi":"10.4062/biomolther.2026.201","DOIUrl":"10.4062/biomolther.2026.201","url":null,"abstract":"<p><p>Estrogen deficiency disrupts the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, resulting in progressive bone loss. Although AMP-activated protein kinase (AMPK) regulates the differentiation and activity of both skeletal cell lineages, the role of endogenous purine metabolites in this process remains poorly understood. We investigated adenine responses and AMPK-associated signaling in skeletal-cell models and assessed histological and protein changes in ovariectomized (OVX) mice. In C2C12 cells and primary bone marrow-derived mesenchymal stem/stromal cells, adenine increased AMPK and cAMP response element-binding protein phosphorylation; upregulated runt-related transcription factor 2, alkaline phosphatase, collagen I, and osteopontin; and enhanced alkaline phosphatase staining and matrix mineralization. In C2C12 cells, Compound C and AMPKα knockdown attenuated these osteogenic responses. In receptor activator of nuclear factor-κB ligand-stimulated RAW264.7 cells and bone marrow-derived macrophages, adenine increased AMPK phosphorylation and reduced osteoclastogenic signaling, tartrate-resistant acid phosphatase staining, and cathepsin K expression. Responses to adenine remained detectable after AMPKα knockdown in RAW264.7 cells. In OVX mice, dietary supplementation with 0.02% adenine for 10 weeks was associated with increased histology-derived trabecular thickness and bone area fraction and changes in bone-associated protein expression. No significant differences were detected in the assessed renal and hepatic indices. These findings support further preclinical investigation of adenine in estrogen-deficiency bone loss.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1441-1455"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13728447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acquired TRAIL Resistance Promotes Cancer Stemness and Malignant Behavior through CD44-SPHK1-STAT3 Signaling in Colorectal Cancer.","authors":"Se Lim Kim, Byung Chul Jin, Seung Young Seo, Sang Wook Kim","doi":"10.4062/biomolther.2026.083","DOIUrl":"10.4062/biomolther.2026.083","url":null,"abstract":"<p><p>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent; however, the frequent emergence of acquired TRAIL resistance limits its therapeutic efficacy in colorectal cancer (CRC). Cancer stem cells (CSCs) contribute to therapeutic resistance, recurrence, and metastatic progression, yet the relationship between TRAIL resistance and CSC enrichment remains unclear. Here, we demonstrate that acquired TRAIL resistance drives CD44-dependent stemness and malignant behavior in CRC. TRAIL-resistant HCT116 cells (HCT116-TR) exhibited increased sphere formation, enhanced motility, and a marked expansion of CD44⁺ cells. CD44⁺ HCT116-TR cells isolated by antibody-based sorting displayed the strongest CSC-like properties, heightened TRAIL resistance, and robust activation of the SPHK1/STAT3 axis, indicating that CD44 upregulation is a major determinant of TRAIL-induced aggressiveness. <i>In vivo</i>, CD44⁺ HCT116-TR cells induced extensive lung metastasis with elevated CD44, p-SPHK1, and p-STAT3 expression, whereas CD44-deficient mice injected with TRAIL-resistant CMT-93 cells showed minimal metastatic burden and reduced pathway activation, confirming the essential role of CD44 in TRAIL-associated metastasis. TCGA colon cancer analysis further revealed CD44 overexpression in tumors and its association with poor overall survival. Collectively, these findings show that acquired TRAIL resistance promotes CD44-mediated CSC expansion and metastatic potential through SPHK1/STAT3 activation, highlighting CD44 as a key therapeutic target in CRC.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1394-1412"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to \"Bioprocess Development of a Human Monoclonal Antibody against MERS-CoV: Analytical and Preclinical Studies\" [Biomol Ther 34(4), 882-890 (2026)].","authors":"Jongsun Lim, Hansaem Lee, Joo-Yeon Lee, Dong-Gyu Jo, Sangwon Hong, So-Young Lee, Byoung Kwon Park, Yungjun Jeong, Jimin Seo, Soya Park, Hwanui Jung, Chan Ki Park, Kyung-Chang Kim, Ickhyun Cho","doi":"10.4062/biomolther.2026.013","DOIUrl":"10.4062/biomolther.2026.013","url":null,"abstract":"","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1472"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149285009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal Stem Cell Therapy for Multiple Sclerosis: Harnessing Immunological Properties.","authors":"Jungeun An, Dongeun Lee, Ji Min Baek, Min Jeong Park, Ye Won Lee, Hye Eum Kim, Kyung Hee Choi, Sung Jean Park, Hee-Sook Jun, Donghee Kim, Ji Woong Choi","doi":"10.4062/biomolther.2026.141","DOIUrl":"10.4062/biomolther.2026.141","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease triggered by damage to the central nervous system (CNS). This CNS damage is caused by the attack of autoreactive T cells against the myelin sheath. Genetic and environmental factors contribute to the development of MS, and the condition causes serious disabilities and exerts substantial health burdens. Although various disease-modifying agents have been developed, they have critical limitations; hence, effective interventions are required. In this context, cell transplantation therapy using mesenchymal stem cells (MSCs), hematopoietic stem cells, neural precursors, neural stem cells, and induced pluripotent stem cells is considered a feasible alternative therapeutic approach. MSCs are adult stem cells that differentiate into multiple lineages and exert immunomodulatory, neuroprotective, and neuroregenerative effects. Therefore, MSCs are considered a promising treatment option for MS owing to their ease of isolation and low immunogenicity. This review summarizes the potential therapeutic benefits of the latest MSC-based approaches for MS treatment in animal models and humans. Furthermore, the review discusses the immunological role of MSCs and future directions for their applications.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1299-1321"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Receptor-Proximal Uncoupling: EGFR-PKC Signaling and Arrestin Deubiquitination-Coupled Nuclear Trafficking in GPCR Signaling Regulation.","authors":"Kyeong-Man Kim","doi":"10.4062/biomolther.2026.132","DOIUrl":"10.4062/biomolther.2026.132","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) constitute the largest family of cell-surface signaling proteins and major therapeutic targets. Their function is critically shaped by desensitization, the attenuation of receptor responsiveness during sustained or repeated stimulation. The canonical model, established in systems such as rhodopsin and the β₂-adrenergic receptor, emphasizes GRK-mediated receptor phosphorylation, arrestin recruitment, and steric inhibition of G-protein coupling, resulting in rapid and largely reversible receptor desensitization. Accumulating evidence, however, indicates that GPCR adaptation can extend beyond this receptor-proximal mechanism. Here, I propose a Two-Level Framework that incorporates an EGFR-dependent adaptive program following sustained activation of selected GPCRs. EGFR serves as an upstream integration hub linking two complementary pathways: a PKC-dependent proximal pathway that mediates receptor-level desensitization, and a Src-PDK1-Akt-USP33 pathway proposed to promote arrestin deubiquitination and subsequent nuclear translocation of arrestin-Gβγ complexes. This translocation may reduce membrane-associated Gβγ availability, thereby contributing to persistent attenuation of receptor signaling, while also influencing nuclear transcriptional activity. The persistent component is revealed by washout-rechallenge paradigms, in which signaling remains impaired despite apparent receptor recovery. Thus, Level II represents an additional layer of GPCR adaptation in which receptor desensitization is accompanied by longer-lasting remodeling of intracellular signaling capacity. Although derived primarily from D2-like and β₂-adrenergic receptor systems, this framework may apply more broadly to GPCRs capable of transactivating EGFR or related receptor tyrosine kinases, providing a broader view of desensitization that integrates receptor-level regulation with network-level adaptation.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":"34 6","pages":"1283-1298"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}