Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Knock-in reporter constructs and drug screening for compounds to restore RKIP expression in cancer","authors":"Sawssen Bouali ,&nbsp;Xunzhen Zheng ,&nbsp;Chris Figy ,&nbsp;Gabriella Lapurga ,&nbsp;Racha Daiea ,&nbsp;Kylie Saxton ,&nbsp;Robert Trumbly ,&nbsp;Gabriel Fenteany ,&nbsp;Kam C. Yeung","doi":"10.1016/j.bbadis.2026.168189","DOIUrl":"10.1016/j.bbadis.2026.168189","url":null,"abstract":"<div><div>RKIP (Raf Kinaes Inhibitory Protein) is ubiquitously expressed in almost all normal tissues of metazoans. Consistent with its negative regulatory role in cell proliferation and survival, RKIP expression is progressively downregulated in cancer accompanied with a worse prognosis and disease outcome. Experiments with cancer cell lines and genetically engineered mice have demonstrated that the expression level of RKIP is a driving factor in determining the disease outcome of cancer, and that restoring RKIP expression is a promising option for therapeutic treatment of low-RKIP-expressing cancers. RKIP expression is mainly regulated at the transcription level such that its expression is tuned down, but not shut off, and is poised to be reactivated. In this study we developed a RKIP gene promoter knock-in reporter breast cancer cell line to screen for compounds that can regulate RKIP transcription in cancer. Using this modified cell line, we were able to identify eight FDA approved compounds that increase RKIP promoter activity by a minimum of 2-fold and can potentially be re-purposed for therapeutic treatment of low-RKIP-expressing breast cancer.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168189"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucosamine suppresses hepatocellular carcinoma progression through dual inhibition of cell cycle progression and nucleotide metabolism","authors":"Yan-lai Zhang ,&nbsp;Jia-xin Yin ,&nbsp;Qun Liu ,&nbsp;De-ao Gong ,&nbsp;Lu-yi Huang ,&nbsp;Ni Tang ,&nbsp;Kai Wang","doi":"10.1016/j.bbadis.2026.168179","DOIUrl":"10.1016/j.bbadis.2026.168179","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver cancer with limited treatment options and poor prognosis. Glucosamine (GlcN), a widely used dietary supplement, demonstrates anti-inflammatory properties but its antitumor potential in HCC remains unknown. Here, we report that GlcN inhibits HCC cell proliferation and migration in a dose-dependent manner in vitro and suppresses orthotopic tumor growth in vivo. Mechanistically, integrated transcriptomics and functional validation revealed that GlcN induces cell cycle arrest in G0/G1 phase by inhibition of E2F1 transcriptional activity. Untargeted metabolomics identified profound nucleotide metabolism disruption, characterized by adenosine triphosphate (ATP) depletion, and partial reversal via nucleoside rescue. Notably, GlcN potentiates the inhibitory efficacy of lenvatinib both in vitro and in vivo. This synergistic effect was further validated in murine models, with the combined GlcN and lenvatinib treatment showing markedly enhanced HCC suppression than monotherapies. Collectively, our findings suggest GlcN as a potential therapeutic agent for HCC and underscore its chemosensitizing potential when combined with lenvatinib. Given GlcN's established clinical safety, this combination offers a translatable strategy for HCC therapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168179"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dapagliflozin targets RORγt to improve myocardial ischemia-reperfusion injury-induced heart failure by regulating the CD4+ T cell/Th17 cell axis within cardiac tissue","authors":"Yan Wu ,&nbsp;Xuewan Ge ,&nbsp;Dongbiao Yu ,&nbsp;Yaqin Wu ,&nbsp;Chao Shi ,&nbsp;Weiwei Cai ,&nbsp;Yufeng Liao ,&nbsp;Lei Huang ,&nbsp;Fei Ge ,&nbsp;Wei Song ,&nbsp;Ming Xu ,&nbsp;Anping Guo ,&nbsp;Tianlu Shi ,&nbsp;Qichao Luo ,&nbsp;Yao Lu ,&nbsp;Shan Gao","doi":"10.1016/j.bbadis.2026.168185","DOIUrl":"10.1016/j.bbadis.2026.168185","url":null,"abstract":"<div><div>Dapagliflozin (DAPA) is the first sodium-glucose cotransporter 2 (SGLT2) inhibitor to receive approval for clinical use in China. However, the mechanism behind the cardioprotective effects of DAPA remains unclear, as cardiac tissue does not express SGLT2. This study investigated the efficacy of DAPA in alleviating myocardial ischemia-reperfusion (MIR) injury, independent of its glucose-lowering properties. The findings revealed that DAPA significantly improved cardiac function and decreased ventricular remodeling in a murine model of MIR injury-induced heart failure (HF). Furthermore, bioinformatics and cellular thermal shift assays (CETSAs) revealed that retinoid-related orphan receptor gamma t (RORγt) acts as a specific molecular target. Moreover, DAPA alleviated MIR injury-induced increased cardiac CD4⁺ T cells as well as RORγt, interleukin-17 A (IL-17 A), and CD4 levels in cardiac tissue. This immunomodulatory effect was clinically significant, as proportions of peripheral blood T helper 17 (Th17) cells were significantly decreased in post-acute myocardial infarction (post-AMI) HF patients undergoing DAPA therapy. In conclusion, the study investigated the cardioprotective effects of DAPA, demonstrating that it can modulate the cardiac immune micro-environment <em>via</em> RORγt, which regulates the CD4⁺ T cell/Th17 cell axis within cardiac tissue. These findings offer mechanistic validation for the tissue-specific therapeutic effects of DAPA in the heart, establishing pharmacological regulation of immune metabolic pathways as an innovative precision medicine strategy for HF, and highlighting its translational potential.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168185"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncostatin M promotes versican expression in cardiac fibroblasts to facilitate extracellular matrix remodeling","authors":"Yunxiaoxiao Wu ,&nbsp;Ziyu Zeng ,&nbsp;Chenying Xiang ,&nbsp;Xinou Jiang ,&nbsp;Yu Nie ,&nbsp;Yanlu Xu ,&nbsp;Jie Feng","doi":"10.1016/j.bbadis.2026.168153","DOIUrl":"10.1016/j.bbadis.2026.168153","url":null,"abstract":"<div><div>Myocardial injury is accompanied by an acute inflammatory response. Our previous work identified Oncostatin M as a key cytokine promoting heart regeneration through stimulating cardiomyocyte proliferation, while its effects on fibroblasts cannot be ignored. Cytokines are generally recognized to activate profibrotic gene programs in cardiac fibroblasts, a process traditionally regarded as detrimental to functional repair. Here, we showed that OSM enhanced cardiac fibroblasts to express versican, a pro-regenerative ECM component in the heart, through activating gp130/JAK/STAT3 signaling pathway. We determined that OSM steered fibroblasts toward a pro-regenerative state by promoting regenerative extracellular matrix remodeling.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168153"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thoracic aortic aneurysm and dissection: Similarities, differences and pharmacotherapy","authors":"Yan-Ni Hu ,&nbsp;Mi Wang ,&nbsp;Zheng Zhang","doi":"10.1016/j.bbadis.2026.168174","DOIUrl":"10.1016/j.bbadis.2026.168174","url":null,"abstract":"<div><div>Aortic aneurysms and aortic dissections are major diseases affecting the thoracic aorta, with high morbidity and mortality. Thoracic aortic aneurysm (TAA) is characterized by bulge in the weakened aortic wall, which is usually asymptomatic and discovered incidentally during physical examination. Without timely intervention, approximately 50% of patients with TAA progress into aortic dissection. Thoracic aortic dissection (TAD) involves false lumen propagation from aortic intimal tear, with concomitant severe lancinating pain in the chest or back. TAA &amp; TAD are highly similar in classification, predisposed sites, risk factors and causes, owing to the occurrence in the same segment of the aorta. Consequently, the collective term “thoracic aortic aneurysm and dissection (TAAD)” has been frequently used, and the definition of TAA &amp; TAD is deemed interchangeable. However, TAA &amp; TAD have essential differences in etiological causes and pathogenetic mechanisms. The mainstay treatment modalities of TAAD are open surgery or thoracic endovascular aortic repair, whereas targeted pharmacotherapies that can slow down, stop or reverse disease progression are lacking. This review summarizes the current knowledge in key aspects that aid in screening, surveilling, diagnosing and managing TAAD, and discusses similarities and differences between TAA and TAD, as well as pertinent pharmacotherapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168174"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"12,13-diHOME ameliorates MASLD by regulating Sestrin2-mediated AMPK/ULK1/Lipophagy in obese mice","authors":"Kexin Zhang ,&nbsp;Chengxia Kan ,&nbsp;Hongyan Qiu ,&nbsp;Junfeng Shi ,&nbsp;Jian Chen ,&nbsp;Tianpeng Zheng ,&nbsp;Jingwen Zhang ,&nbsp;Yujie Ma ,&nbsp;Sufang Sheng ,&nbsp;Ningning Hou ,&nbsp;Fang Han ,&nbsp;Xiaodong Sun","doi":"10.1016/j.bbadis.2026.168186","DOIUrl":"10.1016/j.bbadis.2026.168186","url":null,"abstract":"<div><div>Obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic lipid accumulation and impaired lipid metabolism. Enhancing lipophagy, the autophagic degradation of lipid droplets, represents a promising therapeutic strategy. Sestrin2, a stress-responsive protein, promotes lipophagy via the AMPK/ULK1 pathway. Here, we investigated the role of 12,13-diHOME, a brown adipose tissue-derived lipid, in modulating MASLD via Sestrin2. Male Sesn2 knockout and wild-type mice were fed a high-fat diet (HFD) and treated with 12,13-diHOME. Metabolic parameters, liver histology, and lipophagy-related protein expression were analyzed. 12,13-diHOME improved insulin sensitivity, reduced plasma triglycerides and free fatty acids, and alleviated hepatic steatosis and fibrosis by enhancing lipophagy in wild-type mice. Mechanistically, 12,13-diHOME increased Sestrin2 expression, activated AMPK/ULK1 signaling, inhibited mTOR phosphorylation, and enhanced lipophagic degradation of lipid droplets. These effects were abolished in Sesn2-deficient mice and cells, demonstrating that Sestrin2 is essential for 12,13-diHOME's protective actions. Our findings identify 12,13-diHOME as a potential therapeutic agent for MASLD via Sestrin2-mediated lipophagy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168186"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived ITIH2 activates PI3KAKT pathway via THBS1 ubiquitination and promotes tumor angiogenesis in hepatocellular carcinoma","authors":"Zijian Liu ,&nbsp;Jingsheng Yuan ,&nbsp;Qiwen Zeng ,&nbsp;Zhenru Wu ,&nbsp;Jian Yang ,&nbsp;Tao Lv","doi":"10.1016/j.bbadis.2026.168175","DOIUrl":"10.1016/j.bbadis.2026.168175","url":null,"abstract":"<div><div>The heterogeneous tumor microenvironment (TME) plays a critical role in the initiation and progression of hepatocellular carcinoma (HCC). Within the TME, tumor vascular endothelial cells (ECs) are key stromal components that drive angiogenesis. However, the molecular mechanisms of interaction relationships between angiogenesis and tumor progression in HCC remain unclear. We performed clustering analysis on scRNA-seq data from two HCC patients (GSE166635) and identified eight distinct cell types using uniform manifold approximation and projection (UMAP). An eight-gene risk signature was established to predict patient prognosis. Using iterative least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression, we developed a risk scoring system and constructed a clinically applicable nomogram with TCGA HCC dataset as training cohort and ICGC HCC dataset as validation cohort. The predictive performance of the model was assessed and validated through calibration and decision curve analysis (DCA). Furthermore, we identified ITIH2 as a novel prognostic biomarker in HCC that may be associated with angiogenesis. Immunohistochemical (IHC) staining of clinical samples verified the prognostic value of ITIH2, which was also correlated with the levels of angiogenesis biomarkers, CD31 and CD34. Interestingly, functional experiments, including colony formation, CCK-8, and flow cytometry assays, revealed that ITIH2 overexpression did not alter tumor cell proliferation or apoptosis. Instead, ITIH2 enhanced the angiogenic capacity of ECs and promoted tumor progression in both in vitro and in vivo experiments. However, overexpression of THBS1 could reverse the function of ITIH2 on ECs and PI3K/AKT signaling pathway. Mechanistically, tumor-derived ITIH2 was associated with activation of the PI3K/AKT signaling pathway in ECs via a ubiquitination-dependent regulation of THBS1. The findings recapitulated that tumor-derived ITIH2 could promote HCC progression by enhancing the angiogenic ability of ECs by activating PI3K/AKT signaling pathway via THBS1 stability mediated by ubiquitination.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168175"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano-curcumin mitigates muscle impairment in hypoxic hindlimb-unloaded mice","authors":"Rizwan Qaisar ,&nbsp;Saeed Ahmad Khan ,&nbsp;Mutasem Rawas-Qalaji ,&nbsp;Firdos Ahmad ,&nbsp;Asima Karim","doi":"10.1016/j.bbadis.2026.168178","DOIUrl":"10.1016/j.bbadis.2026.168178","url":null,"abstract":"<div><h3>Background</h3><div>Skeletal muscle atrophy due to hindlimb unloading (HU) is worsened under hypoxic conditions, mimicking clinical scenarios such as prolonged bed rest and chronic cardiopulmonary disease. Curcumin has therapeutic potential but suffers from poor bioavailability. This study evaluated the efficacy of curcumin encapsulated in zein-casein nanoparticles (Cur <em>Z</em>-CS NP) in mitigating muscle deterioration in HU mice under hypoxia.</div></div><div><h3>Methods</h3><div>Cur Z-CS NP were synthesized and characterized for physicochemical properties and drug release. Male C57BL/6 J mice were divided into normoxic and hypoxic groups, each further split into ground control and HU subgroups, and treated with placebo, free curcumin, or Cur <em>Z</em>-CS NP. Muscle function, histology, and gene expression were assessed in gastrocnemius muscles.</div></div><div><h3>Results</h3><div>Cur Z-CS NP exhibited favorable size, charge, and sustained curcumin release. HU and hypoxia significantly reduced body and muscle weights, as well as grip strength and fiber cross-sectional area (<em>p</em> &lt; 0.05). Cur <em>Z</em>-CS NP treatment reversed these effects, increasing muscle mass and fiber size, and significantly improving grip strength. Myonuclear counts were preserved or elevated in treated HU mice, particularly under hypoxia. Cur <em>Z</em>-CS NP also reduced expression of caspase-1, spliced XBP-1, and MLKL, indicating suppression of apoptosis, ER stress, and necroptosis. Although MND size was decreased in HU hypoxic mice, Cur <em>Z</em>-CS NP partially restored it. Wire hanging time remained unaffected.</div></div><div><h3>Conclusion</h3><div>Cur Z-CS NP mitigates muscle atrophy and cellular stress in HU hypoxic mice, offering a promising therapeutic strategy for muscle wasting under conditions of disuse and hypoxia.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168178"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HER2-dependent paraptosis and ferroptosis induction by cannabidiol in breast cancer cells","authors":"Na Young Kim ,&nbsp;Mina Lee ,&nbsp;Yejin Hong ,&nbsp;Ducdat Le ,&nbsp;Dongwoo Nam ,&nbsp;Jae-Young Um ,&nbsp;Kwang Seok Ahn","doi":"10.1016/j.bbadis.2026.168177","DOIUrl":"10.1016/j.bbadis.2026.168177","url":null,"abstract":"<div><div>HER2 (human epidermal growth factor receptor 2) is a well-established oncogenic driver and therapeutic target in breast cancer. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has demonstrated anticancer potential, yet its mechanisms of action in HER2-positive breast cancer remain insufficiently characterized. In this study, we examined the effects of CBD on HER2-positive (SK-BR-3, BT-474) and HER2-negative (MCF-7, MDA-MB-231) breast cancer cell lines, with a focus on its interaction with HER2. CBD selectively reduced the viability of HER2-positive cells, an effect associated with increased intracellular reactive oxygen species (ROS) and a marked reduction in HER2 protein levels. Mechanistically, CBD triggered non-apoptotic cell death pathways, including paraptosis and ferroptosis, as indicated by the modulation of specific molecular markers such as reduced Alix and elevated ATF4 and CHOP for paraptosis, and downregulated GPX4 and SLC7A11 with upregulated TFRC for ferroptosis. HER2 knockdown attenuated CBD-induced cytotoxicity, while HER2 overexpression sensitized cells to CBD, underscoring the HER2-dependence of these effects. Molecular docking predicts the binding conformation and key interactions of ligand with target proteins providing initial insights into potential molecular recognition. Subsequently, molecular dynamics simulations extend this analysis by assessing the stability, flexibility, and energetic characteristics of the ligand–protein complex within a dynamic biological environment. These findings support a model in which CBD downregulates HER2 and, in a HER2-dependent context, promotes paraptosis and ferroptosis. In addition, docking and molecular dynamics analyses suggested a potential interaction between CBD and HER2, providing mechanistic insights into possible molecular recognition relevant to HER2-positive breast cancer.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168177"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating loss of lean muscle in GLP-1 and dual GLP-1/GIP agonists: Pipeline opportunities and limitations","authors":"Justin Hierholzer ,&nbsp;Harrison Benson ,&nbsp;Heba A. Ewida ,&nbsp;Mahmoud Salama Ahmed","doi":"10.1016/j.bbadis.2026.168172","DOIUrl":"10.1016/j.bbadis.2026.168172","url":null,"abstract":"<div><div>Glucagon-like peptide-1 (GLP-1) receptor and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists drive significant transformation in the landscape for type 2 diabetes and obesity management, yet 15–40% of weight loss in trials like STEP and SURMOUNT stems from lean muscle mass. This catabolic loss impairs glucose disposal, muscle strength, and physical function; elevating risks for the loss of force generating capacity in the skeletal muscles leading to sarcopenia, particularly in elderly patients. Unfortunately, current FDA guidelines emphasize total weight reduction over body composition, featuring an unmet critical need for elucidating strategies to preserve loss of lean muscle. This review will feature the emerging therapeutics to mitigate loss of lean muscle, including selective androgen receptor modulators, myostatin-targeting TGF-β inhibitors, and gene-silencing siRNA therapies. Despite promising preclinical and early clinical data, limitations persist, including reliance on parenteral biologics, limited mechanistic diversity, short trial durations, and sparse functional outcome data. Future research must prioritize precise muscle assessments, body composition, long-term trials, and accessible interventions integrating pharmacotherapy. These advances could redefine weight loss paradigms, ensuring therapeutic efficacy aligns with optimal body composition and patient outcomes.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168172"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146055151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}